Novel thiazine derivatives

ABSTRACT

A compound having 3-oxo-3,4-dihydro-2H-1,4-thiazine 4-tetrahydropyrazine as a main skeleton. The compound is a chymase inhibitor and is represented by the following formula [I] and salts thereof:  
                 
 
     In the formula [I], X is S; R 1  and R 2  are H, alkyl, cycloalkyl or aryl; R 3  and R 4  are H, alkyl, cycloalkyl, aryl or an aromatic heterocycle; R 5  is H, alkyl, cycloalkyl, aryl or -A 3 -A 4 -R 7 ; R 6  is H, alkyl, cycloalkyl, hydroxy, alkoxy, aryl, aryloxy or an aromatic heterocycle; R 7  is H, alkyl, hydroxy, alkoxy, aryl, aryloxy, amino, alkylamino, arylamino, an aromatic heterocycle or a nonaromatic heterocycle; A 1  is alkylene; A 2  is carbonyl or sulfonyl; A 3  is alkylene; A 4  is carbonyl or oxalyl; and n is 0 or 1.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This is a divisional application of application Ser. No.10/031,540 filed Jan. 18, 2002, which is a U.S. national phaseapplication of International application PCT/JP00/04964 filed Jul. 26,2000.

TECHNICAL FIELD

[0002] The present invention relates to novel3-oxo-3,4-dihydro-2H-1,4-thiazine derivatives or2-oxo-1,2,3,4-tetrahydropyrazine derivatives being useful aspharmaceuticals.

BACKGROUND ART

[0003] Compounds having 3-oxo-3,4-dihydro-2H-1,4-thiazine or2-oxo-1,2,3,4-tetrahydropyrazine as a main skeleton, which are compoundshaving one double bond in their ring, have scarcely been studied. Therewere only reports concerning a study of introducing a phenyl group intothe 5th-position of 3-oxo-3,4-dihydro-2H-1,4-thiazine derivatives(Japanese Laid-open Patent Publication No. 275869/1990), a study ofsynthesis of 2-oxo-1,2,3,4-tetrahydropyrazine derivatives as syntheticintermediates of 1,5-imino-3-benzoazocine derivatives aiming atanalgesics or antitussives (Japanese Laid-open Patent Publication No.35176/1983) and the like.

[0004] Much less, there has been no report relating to a study whereinvarious substituents are introduced into a nitrogen atom at the4th-position of the 3-oxo-3,4-dihydro-2H-1,4-thiazine derivatives orinto a nitrogen atom at the 1 st-position of the2-oxo-1,2,3,4-tetrahydropyrazine derivatives and their pharmaceuticalutility is examined. In particular, compounds having carboxy-loweralkylene converted into amide, which are subjects of the presentinvention, have not been studied at all.

[0005] It is a very interesting subject to synthesize novel compoundshaving 3-oxo-3,4-dihydro-2H-1,4-thiazine or2-oxo-1,2,3,4-tetrahydropyrazine as a main skeleton wherein varioussubstituents are introduced into the nitrogen atom in their ring and tostudy their pharmaceutical utility.

DISCLOSURE OF THE INVENTION

[0006] The present inventors studied preparation of various novelcompounds having 3-oxo-3,4-dihydro-2H-1,4-thiazine or2-oxo-1,2,3,4-tetrahydropyrazine as a main skeleton. Targets of thestudy are 1) to prepare novel compounds wherein carboxy-lower alkyleneconverted into amide is introduced into a nitrogen atom at the4th-position of 3-oxo-3,4-dihydro-2H-1,4-thiazine derivatives or into anitrogen atom at the 1St-position of 2-oxo-1,2,3,4-tetrahydropyrazinederivatives, and 2) to prepare novel compounds wherein varioussubstituents are introduced into a nitrogen atom at the 4th-position ofthe 2-oxo-1,2,3,4-tetrahydropyrazine derivatives. As a result, thepresent inventors succeeded in preparing many novel compounds asmentioned later. Studying their pharmacological actions, these novelcompounds were found to exhibit chymase inhibitory effects and to beuseful as pharmaceuticals. The present inventors succeeded also inpreparing novel compounds which are useful as synthetic intermediates ina process of the preparation of the above-mentioned3-oxo-3,4-dihydro-2H-1,4-thiazine derivatives or2-oxo-1,2,3,4-tetrahydropyrazine derivatives.

[0007] The present invention relates to compounds represented by thefollowing general formula [I] and salts thereof (hereinafter referred toas “the present compound” as far as there is no proviso), pharmaceuticalcompositions comprising them as active ingredients, and compoundsrepresented by the general formula [II] being useful as syntheticintermediates of the present compound and salts of the intermediates(hereinafter referred to as “the present synthetic intermediate” as faras there is no proviso),

[0008] wherein

[0009] X is S or R⁶-(A₂)_(n)-N,

[0010] R¹ and R², being the same or different, are hydrogen, loweralkyl, cycloalkyl or aryl,

[0011] R³ and R⁴, being the same or different, are hydrogen, loweralkyl, cycloalkyl, aryl or aromatic heterocycles,

[0012] R⁵ is hydrogen, lower alkyl, cycloalkyl, aryl or -A₃-A₄-R⁷,

[0013] R⁶ is hydrogen, lower alkyl, cycloalkyl, hydroxy, lower alkoxy,aryl, aryloxy or an aromatic heterocycle,

[0014] R⁷ is hydrogen, lower alkyl, hydroxy, lower alkoxy, aryl,aryloxy, amino, lower alkylamino, arylamino, an aromatic heterocycle ora nonaromatic heterocycle,

[0015] n is 0 or 1,

[0016] A₁ is lower alkylene,

[0017] A₂ is carbonyl or sulfonyl,

[0018] A₃ is lower alkylene, and

[0019] A₄ is carbonyl or oxalyl.

[0020] Each lower alkyl defined above can be substituted by halogen,hydroxy, lower alkoxy, aryl or aryloxy.

[0021] Each lower alkoxy defined above can be substituted by aryl.

[0022] Each lower alkylene defined above can be substituted by aryl. Thesame definitions are applied hereinafter.

[0023] [wherein Q is —CH(OH)CO— or —CH(OH)—. The same definition isapplied hereinafter.]

[0024] The groups defined above have the following meanings through thewhole present specification.

[0025] The halogen is fluorine, chlorine, bromine or iodine.

[0026] The lower alkyl is straight-chain or branched alkyl having one tosix carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl or isohexyl.The lower alkyl can be substituted by halogen, cycloalkyl, hydroxy,lower alkoxy, aryl or aryloxy.

[0027] The cydoalkyl is cycloalkyl having three to eight carbon atomssuch as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cydoheptyl orcyclooctyl. The cycloalkyl can be substituted by halogen, lower alkyl,cycloalkyl, hydroxy, lower alkoxy, aryl or aryloxy.

[0028] The lower alkoxy is straight-chain or branched alkoxy having oneto six carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy,t-butoxy or hexyloxy. The lower alkoxy can be substituted by halogen,cydoalkyl, hydroxy, lower alkoxy, aryl or aryloxy.

[0029] The lower alkylene is straight-chain or branched alkylene havingone to six carbon atoms such as methylene, ethylene, trimethylene, tetraethylene, pentamethylene, hexamethylene, methylmethylene,dimethylmethylene, ethylmethylene, propylmethylene, isopropylmethylene,butylmethylene, isobutylmethylene, sec-butylmethylene,tert-butylmethylene, tert-butylethylene, dimethylethylene,ethylethylene, propylethylene, isopropylethylene, methyltrimethylene orpropylene. The lower alkylene can be substituted by halogen, cycloalkyl,hydroxy, lower alkoxy, aryl or aryloxy.

[0030] The aryl is a monocyclic or condensed aromatic hydrocarbon suchas phenyl or naphthyl. The aryl can be substituted by halogen, loweralkyl, cycloalkyl, hydroxy, lower alkoxy, aryl, aryloxy, acyl or nitro.

[0031] The aromatic heterocycle is an aromatic heterocycle having oneheteroatom in the ring such as pyrrole, furan, thiophene or pyridine; anazole aromatic heterocycle such as imidazole, oxazole, thiazole,pyrazole, isoxazole or isothiazole; an aromatic heterocycle having twonitrogen atoms in the ring such as pyrazine or pyrimidine; or acondensed aromatic heterocycle such as indole, isoindole, benzimidazole,benzoxazole, benzothiazole or quinoline. Each aromatic heterocycle canbe substituted by halogen, lower alkyl, cycloalkyl, hydroxy, loweralkoxy, aryl, aryloxy or acyl.

[0032] The nonaromatic heterocycle is a saturated nonaromaticheterocycle having one heteroatom in the ring such as pyrrolidine,tetrahydrofuran, tetrahydrothiophene, piperidine, tetrahydropyran orhomopiperazine; a saturated nonaromatic heterocycle having twoheteroatoms in the ring such as imidazolidine, oxazolidine,thiazolidine, pyrazolidine, piperazine, morpholine, thiomorpholine,homopiperidine or homomorpholine; an unsaturated nonaromatic heterocyclehaving one heteroatom in the ring such as pyrroline, dihydrofuran,dihydrophene tetrahydropiperidine, dihydropiperidine, dihydropyran orpyran; or an unsaturated nonaromatic heterocycle having two heteroatomssuch as imidazoline, oxazoline, thiazoline or pyrazoline. Eachnonaromatic heterocycle can be substituted by halogen, lower alkyl,cycloalkyl, hydroxy, lower alkoxy, aryl, aryloxy or carbamoyl.

[0033] The acyl is lower alkanoyl having two to six carbon atoms such asacetyl, propionyl, butyryl, pivaloyl or pentanecarbonyl, or benzoyl. Thephenyl ring of the benzoyl can be substituted by halogen, lower alkyl,cydoalkyl, hydroxy, lower alkoxy, aryl, aryloxy, acyl or nitro.

[0034] When the present compound or the present synthetic intermediatehas free hydroxy or free amino, —NHR (wherein R is lower alkyl) orimino, they can be protected with a general protecting group.

[0035] General protecting groups of hydroxy can be used as theprotecting group of hydroxy. Specific examples of the protecting groupare acyl such as formyl, lower alkanoyl, halogeno-lower alkanoyl orbenzoyl; alkoxycarbonyl such as lower alkoxycarbonyl or phenyl-loweralkoxycarbonyl; substituted alkyl derivatives such as allyl, loweralkoxy-lower alkyl, substituted lower alkoxy-lower alkyl, phenyl-loweralkyl, tetrahydropyranyl and tetrahydrofuranyl; and substituted silylsuch as lower alkylsilyl or phenylsilyl. Each phenyl ring of theabove-mentioned benzoyl, phenyl-lower alkoxycarbonyl, phenyl-lower alkyland phenylsilyl can be substituted by halogen, lower alkyl, lower alkoxyor nitro.

[0036] More specific examples of the protecting group of hydroxy areacyl such as formyl, acetyl, pivaloyl, monochloroacetyl,trichloroacetyl, trifluoroacetyl, benzoyl, methoxycarbonyl,ethoxycarbonyl, isobutoxycarbonyl, t-butoxycarbonyl orbenzyloxycarbonyl; substituted alkyl derivatives such as allyl,methoxymethyl, 1-ethoxyethyl, 2-methoxyethoxymethyl, benzyloxymethyl,benzyl, 4-methoxybenzyl, trityl, 2-tetrahydropyranyl and2-tetrahydrofuranyl; and substituted silyl such as trimethylsilyl,triethylsilyl, triisopropylsilyl, t-butyldimethylsilyl ort-butyldiphenylsilyl.

[0037] The protecting groups of amino or imino can be those which arewidely used as protecting groups of amine. Specific examples of theprotecting group are acyl such as formyl, lower alkanoyl, halogeno-loweralkanoyl, benzoyl, lower alkoxycarbonyl, substituted loweralkoxycarbonyl or phenoxycarbonyl; substituted alkyl derivatives such asallyl, phenyl-lower alkyl and benzoyl-lower alkyl; substituted sulfonylsuch as lower alkylsulfonyl or phenylsulfonyl; and lower alkoxy. Eachphenyl ring of the above-mentioned benzoyl, phenoxycarbonyl,phenyl-lower alkyl, benzoyl-lower alkyl and phenylsulfonyl can besubstituted by halogen, lower alkyl, lower alkoxy or nitro.

[0038] More specific examples of the protecting group of amino or iminoare acyl such as formyl, acetyl, trichloroacetyl, trifluoroacetyl,benzoyl, methoxycarbonyl, ethoxycarbonyl, isobutoxycarbonyl,t-butoxycarbonyl, allyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl,benzyloxycarbonyl, diphenylmethoxycarbonyl or phenoxycarbonyl;substituted alkyl derivatives such as allyl, benzyl and trityl; andsubstituted sulfonyl such as benzenesulfonyl,2,4,6-trimethylbenzenesulfonyl or toluenesulfonyl.

[0039] Preferred examples of the present compound are compounds whereinthe group(s) is (are) the followings in the compounds represented by thegeneral formula [I] or salts thereof;

[0040] (1a) X is a group selected from S and R⁶-(A₂)_(n)-N; and/or

[0041] (2a) R¹ and R², being the same or different, are groups selectedfrom hydrogen, lower alkyl, cycloalkyl and aryl, wherein the lower alkylcan be substituted by a group selected from hydroxy and lower alkoxy;and/or

[0042] (3a) R³ and R⁴, being the same or different, are groups or ringsselected from hydrogen, lower alkyl, aryl and aromatic heterocycles,wherein the aryl can be substituted by a group selected from halogen,lower alkoxy and lower alkoxycarbonyl, and the lower alkoxy can besubstituted by aryl; and/or

[0043] (4a) R⁵ is -A₃-A₄R₇; and/or.

[0044] (5a) R⁶ is a group or a ring selected from hydrogen, lower alkyl,cycloalkyl, lower alkoxy, aryl and aromatic heterocycles, wherein thelower alkyl can be substituted by a group selected from alkoxy, aryl andaryloxy, each lower alkoxy can be substituted by aryl, and each aryl canbe substituted by a group selected from halogen, lower alkoxy and nitro;and/or

[0045] (6a) R⁷ is a group or a ring selected from hydrogen, lower alkyl,hydroxy, lower alkoxy, aryloxy, amino, lower alkylamino, aromaticheterocycles and nonaromatic heterocycles, wherein the cydoalkyl can besubstituted by lower alkyl, the lower alkyl can be substituted byhalogen or hydroxy, and the nonaromatic heterocycles can be substitutedby lower alkyl, cydoalkyl or aminocarbonyl; and/or

[0046] (7a) n is 1; and/or

[0047] (8a) A₁ is lower alkylene, wherein the lower alkylene can besubstituted by aryl; and/or

[0048] (9a) A₂ is a group selected from carbonyl and sulfonyl; and/or

[0049] (10a) A₃ is lower alkylene, wherein the lower alkylene can besubstituted by aryl, and the aryl can be substituted by halogen; and/or

[0050] (11a) A₄ is a group selected from carbonyl and oxalyl.

[0051] Namely,

[0052] Compounds defined by above (1a) in the compounds represented bythe general formula [I] or salts thereof,

[0053] Compounds defined by above (2a) in the compounds represented bythe general formula [I] or salts thereof,

[0054] Compounds defined by above (3a) in the compounds represented bythe general formula [I] or salts thereof,

[0055] Compounds defined by above (4a) in the compounds represented bythe general formula [I] or salts thereof,

[0056] Compounds defined by above (5a) in the compounds represented bythe general formula [I] or salts thereof,

[0057] Compounds defined by above (6a) in the compounds represented bythe general formula [I] or salts thereof,

[0058] Compounds defined by above (7a) in the compounds represented bythe general formula [I] or salts thereof,

[0059] Compounds defined by above (8a) in the compounds represented bythe general formula [I] or salts thereof,

[0060] Compounds defined by above (9a) in the compounds represented bythe general formula [I] or salts thereof,

[0061] Compounds defined by above (10a) in the compounds represented bythe general formula [I] or salts thereof,

[0062] Compounds defined by above (11a) in the compounds represented bythe general formula [I] or salts thereof, and

[0063] Compounds defined by any combinations of two or more of above(1a), (2a), (3a), (4a), (5a), (6a), (7a), (8a), (9a), (10a) and (11a) inthe compounds represented by the general formula [I] or salts thereof.

[0064] More preferred examples of the present compound are compoundswherein the group(s) is (are) the followings in the compoundsrepresented by the general formula [I] or salts thereof,

[0065] (1a) X is a group selected from S and R⁶-(A₂)_(n)-N; and/or

[0066] (2a) R¹ and R², being the same or different, are groups selectedfrom hydrogen and lower alkyl; and/or

[0067] (3a) R³ and R⁴, being the same or different, are groups selectedfrom hydrogen and aryl, wherein the aryl can be substituted by a groupselected from halogen, lower alkoxy and lower alkoxycarbonyl, and thelower alkoxy can be substituted by aryl; and/or

[0068] (4a) R⁵ is -A₃-A₄-R⁷; and/or

[0069] (5a) R⁶ is a group selected from lower alkyl, lower alkoxy, aryland aromatic heterocycles, wherein the lower alkyl can be substituted bya group selected from lower alkoxy, aryl and aryloxy; and/or

[0070] (6a) R⁷ is a group selected from lower alkyl, lower alkoxy,aromatic heterocycles and nonaromatic heterocycles, wherein the loweralkyl can be substituted by halogen, and the nonaromatic heterocyclescan be substituted by lower alkyl; and/or

[0071] (7a) n is 1; and/or

[0072] (8a) A₁ is lower alkylene; and/or

[0073] (9a) A₂ is a group selected from carbonyl and sulfonyl; and/or

[0074] (10a) A₃ is lower alkylene, wherein the lower alkylene can besubstituted by aryl; and/or

[0075] (11a) A₄ is a group selected from carbonyl and oxalyl.

[0076] Namely,

[0077] Compounds defined by above (1a) in the compounds represented bythe general formula [I] or salts thereof,

[0078] Compounds defined by above (2a) in the compounds represented bythe general formula [I] or salts thereof,

[0079] Compounds defined by above (3a) in the compounds represented bythe general formula [I] or salts thereof,

[0080] Compounds defined by above (4a) in the compounds represented-bythe general formula [I] or salts thereof,

[0081] Compounds defined by above (5a) in the compounds represented bythe general formula [I] or salts thereof,

[0082] Compounds defined by above (6a) in the compounds represented bythe general formula [I] or salts thereof,

[0083] Compounds defined by above (7a) in the compounds represented bythe general formula [I] or salts thereof,

[0084] Compounds defined by above (8a) in the compounds represented bythe general formula [I] or salts thereof, Compounds defined by above(9a) in the compounds represented by the general formula [I] or saltsthereof,

[0085] Compounds defined by above (10a) in the compounds represented bythe general formula [I] or salts thereof,

[0086] Compounds defined by above (11a) in the compounds represented bythe general formula [I] or salts thereof, and

[0087] Compounds defined by any combinations of two or more of above(1a), (2a), (3a), (4a), (5a), (6a), (7a), (8a), (9a), (10a) and (11a) inthe compounds represented by the general formula [I] or salts thereof.

[0088] Further preferred examples of the present compound are compoundswherein the group(s) is (are) the followings in the compoundsrepresented by the general formula [I] or salts thereof;

[0089] (1a) X is a group selected from S and R⁶-(A₂)_(n)-N; and/or

[0090] (2a) R¹ and R², being the same or different, are groups selectedfrom hydrogen and isopropyl; and/or

[0091] (3a) R³ and R⁴, being the same or different, are groups selectedfrom hydrogen and phenyl; and/or

[0092] (4a) R⁵ is -A₃-A₄-R⁷; and/or

[0093] (5a) R⁶ is a group or a ring selected from methyl, ethyl,isopropyl, t-butyl, methoxymethyl, phenyl, phenethyl, benzyloxy andpyridine; and/or

[0094] (6a) R⁷ is a group or a ring selected from methyl,trifluoromethyl, heptafluoromethyl, methoxy, isopropyloxy, pyrrolidine,dihydrofuran, oxazoline, 4,4-dimethyloxazoline, thiazoline,5,5-dimethylthiazoline, piperidine, piperazine, morpholine, oxazole,thiazole and benzothiazole; and/or

[0095] (7a) n is 1; and/or

[0096] (8a) A₁ is methylene; and/or

[0097] (9a) A₂ is a group selected from carbonyl and sulfonyl; and/or

[0098] (10a) A₃ is phenylmethylmethylene; and/or

[0099] (11a) A₄ is a group selected from carbonyl and oxalyl.

[0100] Namely,

[0101] Compounds defined by above (1a) in the compounds represented bythe general formula [I] or salts thereof,

[0102] Compounds defined by above (2a) in the compounds represented bythe general formula [I] or salts thereof,

[0103] Compounds defined by above (3a) in the compounds represented bythe general formula [I] or salts thereof,

[0104] Compounds defined by above (4a) in the compounds represented bythe general formula [I] or salts thereof,

[0105] Compounds defined by above (5a) in the compounds represented bythe general formula [I] or salts thereof,

[0106] Compounds defined by above (6a) in the compounds represented bythe general formula [I] or salts thereof,

[0107] Compounds defined by above (7a) in the compounds represented bythe general formula [I] or salts thereof,

[0108] Compounds defined by above (8a) in the compounds represented bythe general formula [I] or salts thereof,

[0109] Compounds defined by above (9a) in the compounds represented bythe general formula [I] or salts thereof, Compounds defined by above(10a) in the compounds represented by the general formula [I] or saltsthereof,

[0110] Compounds defined by above (11a) in the compounds represented bythe general formula [I] or salts thereof, and

[0111] Compounds defined by any combinations of two or more of above(1a), (2a), (3a), (4a), (5a), (6a), (7a), (8 a), (9a), (10a) and (11a)in the compounds represented by the general formula [I] or saltsthereof.

[0112] The most preferred examples of the present compound are compoundswherein the group(s) is (are) the followings in the compoundsrepresented by the general formula [I] or salts thereof,

[0113] (1a) X is a group selected from S and R⁶-(A₂)_(n)-N; and/or

[0114] (2a) R¹ and R², being the same or different, are groups selectedfrom hydrogen and isopropyl; and/or

[0115] (3a) R³ and R⁴, being the same or different, are groups selectedfrom hydrogen and phenyl; and/or

[0116] (4a) R⁵ is -A₃-A₄-R⁷; and/or

[0117] (5a) R⁶ is a group or a ring selected from methyl, phenyl andpyridine; and/or

[0118] (6a) R⁷ is a group or a ring selected from trifluoromethyl,isopropyloxy, oxazoline, thiazoline, 4,4-dimethyloxazoline,5,5-dimethylthiazoline and benzothiazole; and/or

[0119] (7a) n is 1; and/or

[0120] (8a) A₁ is methylene; and/or

[0121] (9a) A₂ is carbonyl; and/or

[0122] (10a) A₃ is phenylmethylmethylene; and/or

[0123] (11a) A₄ is a group selected from carbonyl and oxalyl.

[0124] Namely,

[0125] Compounds defined by above (1a) in the compounds represented bythe general formula [I] or salts thereof,

[0126] Compounds defined by above (2a) in the compounds represented bythe general formula [I] or salts thereof, Compounds defined by above(3a) in the compounds represented b the general formula [I] or saltsthereof,

[0127] Compounds defined by above (4a) in the compounds represented bythe general formula [I] or salts thereof,

[0128] Compounds defined by above (5a) in the compounds represented bythe general formula [I] or salts thereof,

[0129] Compounds defined by above (6a) in the compounds represented bythe general formula [I] or salts thereof,

[0130] Compounds defined by above (7a) in the compounds represented bythe general formula [I] or salts thereof,

[0131] Compounds defined by above (8a) in the compounds represented bythe general formula [I] or salts thereof,

[0132] Compounds defined by above (9a) in the compounds represented bythe general formula [I] or salts thereof,

[0133] Compounds defined by above (10a) in the compounds represented bythe general formula [I] or salts thereof,

[0134] Compounds defined by above (11a) in the compounds represented bythe general formula [I] or salts thereof, and

[0135] Compounds defined by any combinations of two or more of above(1a), (2a), (3a), (4a), (5a), (6a), (7a), (8a), (9a), (10a) and (11a) inthe compounds represented by the general formula [I] or salts thereof.

[0136] The salts in the present invention refer to any pharmaceuticallyacceptable salts and are exemplified by salts with an inorganic acidsuch as hydrochloric acid, nitric acid or sulfuric acid, salts with anorganic acid such as acetic acid, fumaric acid, maleic acid or tartaricacid, salts with an alkaline metal or an alkaline earth metal such assodium, potassium or calcium, quaternary salts with an organohalogencompound, and the like.

[0137] Preferred examples of the quaternary salt are quaternary saltswith an alkyl halide derivative. Specific examples of the quaternarysalt are quaternary salts with methyl iodide, benzyl bromide, methylbromoacetate, 2-bromoacetamide, 2-iodoacetamide,4-bromo-2-methyl-2-butene, farnesyl bromide, geranyl bromide or thelike.

[0138] Further, some of the present compounds or the presentintermediates have asymmetric carbon atoms. When there are geometricisomers or optical isomers, these isomers are also included in the scopeof the present invention.

[0139] The present compounds or the present intermediates can take theform of solvates such as hydrates.

[0140] The present compounds represented by the general formula [I] canbe synthesized, for example, by the following typical method oraccording to this method.

[0141] The above-mentioned method includes the following three syntheticroutes.

[0142] Synthetic route A: compound [III]→compound [I]

[0143] Synthetic route B: compound [III]→compound [II]→compound [I]

[0144] Synthetic route C: compound [III]→compound [IV]→compound[V]→compound [VI]→compound [II]→compound [I]

[0145] These synthetic routes are specifically described hereinafter.

[0146] Synthetic Method A:

[0147] The compound [III] and the amine derivative [VII] are condensedby a general method for formation of amide linkage to give the presentcompound [I]. Specific examples of the method are a method using adehydrating condensing agent such as1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride or1,3-dicyclohexylcarbodiimide, and a method using mixed acid anhydridesuch as isobutyl chloroformate.

[0148] Synthetic method B:

[0149] The compound [III] and the amine derivative [VIII] are condensedby a method similar to the synthetic method A to give the presentsynthetic intermediate [II]. Then, the hydroxyl group of the compound[II] is oxidized by a general oxidation method (for example, Swernoxidation method, Moffatt oxidation method, Dess-Martin oxidation methodor the like) to give the present compound [I].

[0150] Synthetic method C:

[0151] The compound [I] and the amine derivative [IX] are condensed by amethod similar to the synthetic method A to give the compound [IV].Then, the hydroxyl group of the compound [IV] is oxidized by a generaloxidation method (for example, Swern oxidation method, Moffatt oxidationmethod, Dess-Martin oxidation method or the like) to give the compound[V]. Further, the compound [V] is reacted with potassium cyanide to givethe cyanohydrin derivative [VI]. Then, the compound [VI] is reacted withacetyl chloride and a lower alcohol (for example, ethanol or the like)to convert it into an iminoester derivative, and this derivative isreacted with the aminoalcohol derivative [α]to give the presentsynthetic intermediate [II]. Then, this intermediate is oxidized by thesame oxidation method as the synthetic method B to give the presentcompound [I].

[0152] The amine derivatives [VII], [VIII] and [IX] to be used in thesemethods can be synthesized by the method described in WO 93/25574 or J.Med. Chem., 33, 2707-2714 (1990).

[0153] The above-mentioned compound [III] can be synthesized, forexample, by the following typical method or similar methods.

[0154] In the above synthetic route, X is S or R⁶-(A₂)_(n)-N, and Y is—SH, —NH₂ or —NHR (wherein R is R⁶-(A₂)_(n)). R_(a) and R_(b), being thesame or different, are lower alkyl.

[0155] This synthetic route is described specifically.

[0156] The compound [XI] is reacted with the compound [XVI] under abasic condition to give the compound [XII]. (When Y is —NH₂, thecompound [XI] is reacted with the compound [XVI] and then with the acidanhydride [XVIII] or the acid chloride [XIX] to give the compound[XII].) Then, the compound

[0157] [XII] is reacted with ammonia to convert it into the amidederivative [XIII], and this derivative is cyclized by refluxing it underan acidic condition to give the compound [XIV]. Then, after adding ametal hydride, the compound

[0158] [XIV] is reacted with the compound [XVII] to give the compound[XV]. The ester moiety of the compound [XV] is hydrolyzed under a basiccondition to give the compound [III].

[0159] The compound [III] can also be synthesized by a method describedin Japanese Laid-open Patent Publication No. 35176/1983.

[0160] The compound [II] is a novel compound and a useful syntheticintermediate of the present compound [I]. In the formula, X, R¹, R², R³,R⁴, R⁷, A₁ and A₃ have the same definitions as in the general formula[I]. Preferred examples of the present synthetic intermediate [II] arecompounds corresponding to the above-mentioned preferred examples of thepresent compound [I].

[0161] The compounds [I] and [II] obtained by the above-mentionedmethods can be converted into the above-mentioned salts by theconventional method. As mentioned above, when there are diastereomersand optical isomers in the compounds represented by the generalformulae, all these isomers are included in the present invention. Whenan optically active starting material is used, a single diastereomer anda single optical isomer are obtained. When a racemate is used as astarting material, respective isomers can be separated by generalmethods such as optical resolution methods.

[0162] As described in the section of “Background Art”, compounds having3-oxo-3,4-dihydro-2H-1,4-thiazine or 2-oxo-1,2,3,4-tetrahydropyrazine asa main skeleton have scarcely been studied.

[0163] Namely, the present compounds are novel compounds which areunknown in literatures. Features of their chemical structure composing amain skeleton are shown in the general formula [I]. The targets of thestudy are 1) to prepare the novel compounds wherein carboxy-loweralkylene converted into amide is introduced into the nitrogen atom atthe 4th-position of the 3-oxo-3,4-dihydro-2H-1,4-thiazine derivatives orinto the nitrogen atom at the 1St-position of the2-oxo-1,2,3,4-tetrahydropyrazine derivatives, and 2) to prepare thenovel compounds wherein the various substituents are introduced into thenitrogen atom at the 4th-position of the2-oxo-1,2,3,4-tetrahydropyrazine derivatives.

[0164] Focusing attention on these two points and studying precisely,the present inventors have succeeded in preparing the many novelcompounds.

[0165] Administration methods of drugs can be a method of administeringactive compounds themselves or a method of administering the drugs inthe form to be decomposed in vivo and to be converted into the activecompounds, namely in the form of prodrugs. Both are widely used Thepresent compounds have a carboxyl group in their molecule. The presentcompounds can be administered in the form of the carboxylic acid andalso in the form of an ester which can be converted into the carboxylicacid by hydrolysis. When the present compounds have an amino group or ahydroxyl group in their molecule, the present compounds can beadministered with these groups protected with suitable protectinggroups.

[0166] Further, in order to find utility of the present compounds,chymase inhibitory effects of the present compounds were studied.Details will be described later in the part of “Pharmacological Test”.The present compounds exhibited excellent chymase inhibitory effects.Chymase has been reported to exist in systemic tissues such as gut, skinand lung centering around tissues of cardiovascular system and toparticipate in outbreaks of physiologic functions such as cardiovascularlesion, inflammation, immune functions and tissue remodeling (Journal ofClinical and Experimental Medicine, 743 (10), 743 (1995)). Chymase hasbeen reported to participate also in outbreaks of cardiac infarction,heart failure, blood vessel restenosis after PTCA and the like (BloodVessel & Endothelium, 5 (5), 37 (1995)), hypertension (FEBS Lett., 406,301(1997)), diabetes complication (Biol. Chem., Hoppe Seyler (GERMANY,WEST), 369 Suppl., p299), allergic diseases (Nobuhiko Katsunuma,“Intracellular Proteolysis”, p. 101-106), asthma (J. Pharmacol. Exp.Ther., 244 (1), 133 (1987)) and the like. Chymase inhibitors areexpected to be effective in treating these diseases.

[0167] The present compound can be administered orally or parenterally.Examples of dosage forms are tablets, capsules, granules, powders,injections, eyedrops and the like. The present compound can beformulated into preparations by the conventional methods. For example,oral preparations such as tablets, capsules, granules and powders can beprepared by using optionally a diluent such as lactose, crystallinecellulose, starch or vegetable oil; a lubricant such as magnesiumstearate or talc; a binder such as hydroxypropylcellulose or polyvinylpyrrolidone; a disintegrator such as calcium carboxymethylcellulose orlow-substituted hydroxypropylmethylcellulose; a coating agent such ashydroxypropylmethylcellulose, macrogol or silicone resin; or a filmforming agent such as a gelatin film. Eyedrops can be prepared by usingoptionally an isotonic agent such as sodium chloride or concentratedglycerine; a buffer such as sodium phosphate or sodium acetate; asurfactant such as polyoxyethylenesorbitan monooleate, polyoxyl 40stearate or polyoxyethylene hydrogenated castor oil; a stabilizer suchas sodium citrate or disodium edetate; or a preservative such asbenzalkonium chloride or paraben, pH can be in a range acceptable forophthalmic preparations, and it is more preferably in a range of 4 to 8.

[0168] The dosage of the present compound can be selected suitablydepending on symptoms, age, dosage form and the like. In case of theoral preparations, the present compound can be administered once toseveral times per day with a daily dose of 0.1 to 5000 mg, preferably 1to 1000 mg.

BEST MODE FOR CARRYING OUT THE INVENTION

[0169] Examples of preparations and formulations and results ofpharmacological test of the present invention are shown below. Theseexamples do not limit the scope of the invention, but are intended tomake the invention more clearly understandable.

REFERENCE EXAMPLES

[0170] Preparation of Compounds

[0171] The following Reference Examples 1 to 33 show examples of thesynthesis of the amine derivatives [VII] or the aminoalcohol derivatives

[0172] [VIII] described in detail in the section of “Disclosure of theInvention”.

Reference Example 1

[0173] (2S)-2-(tert-Butoxycarbonyl)amino-3-phenyl-1-propanol (ReferenceCompound No. 1-1)

[0174] A solution of di-tert-butyl dicarbonate (1.44 g) intetrahydrofuran (5 ml) is added dropwise to a solution of(2S)-2-amino-3-phenyl-1-propanol (1.00 g) in tetrahydrofuran (15 ml),and the mixture is stirred for 30 minutes. Then, the reaction mixture isconcentrated under reduced pressure, and the resulting residue ispurified by silica gel column chromatography to give the titledreference Compound (1.70 g).

[0175] mp 95.2-96.7° C.

[0176] [α]_(D) ²⁰ −26.9° (c=1.0, methanol)

[0177] IR(KBr,cm⁻¹)3355, 1688, 1529, 1444, 1367, 1316, 1270, 1252, 1169,100{overscore (6)}, 702

[0178] The following compound is obtained by a method similar toReference Example 1.

[0179] (2S)-2-(tert-Butoxycarbonyl)amino-4-methyl-1-pentanol (ReferenceCompound No. 1-2)

[0180] [α]_(D) ²⁰ −25.2° (c=1.0, methanol)

[0181] IR(Film,cm⁻¹)3337, 2957, 2870, 1685, 1522, 1469

Reference Example 2

[0182] (2S)-2-(tert-Butoxycarbonyl)amino-3-phenylpropanal (ReferenceCompound No. 2-1)

[0183] Thethylamine (17 ml) is added to a solution of(2S)-2-(tert-butoxycarbonyl)amino-3-phenyl-1-propanol (5.00 g, ReferenceCompound No. 1-1) in dimethyl sulfoxide (100 ml). Then, a sulfurtrioxide-pyridine complex (11.1 g) is added to the mixture, and thewhole is stirred for 40 minutes. Water is added to the reaction mixture,and the whole is extracted with diethyl ether. The extract is washedwith a saturated aqueous ammonium chloride solution, water, a saturatedaqueous sodium hydrogencarbonate solution and saturated brinesuccessively and dried over anhydrous magnesium sulfate. The extract isconcentrated under reduced pressure, and the resulting residue ispurified by silica gel column chromatography to give the titledreference Compound (4.48 g).

[0184] IR(KBr,cm⁻¹) 1731, 1672, 1561

[0185] The following compounds are obtained by a method similar toReference Example 2.

[0186] (2S)-2-(tert-Butoxycarbonyl) amino-4-methylpentanal (ReferenceCompound No. 2-2)

[0187] [α]_(D) ²⁰ +1.8° (c=0.99, chloroform)

[0188] IR(Film,cm⁻¹)3349, 2960, 2871, 1708, 1512, 1391

[0189] (2S)-2-(Benzyloxycarbonyl)amino-3-phenylpropanal (ReferenceCompound No. 2-3)

[0190] IR(Film,cm⁻¹)3331, 3063, 3030, 2949, 1706, 1604, 1585, 1517, 1454

Reference Example 3

[0191] (2RS,3S)-3-(tert-Butoxycarbonyl)amino-2-hydroxy-4-phenylbutanenitrile(Reference Compound No. 3-1)

[0192] A solution of sodium hydrogensulfite (0.92 g) in water (5 ml) isadded to a suspension of(2S)-2-(tert-butoxycarbonyl)amino-3-phenylpropanal (2.00 g, ReferenceCompound No. 2-1) in water (20 ml) under ice cooling, then thetemperature is raised to room temperature, and the mixture is stirredovernight. Ethyl acetate (100 ml) is added to the mixture, and the wholeis stirred for one hour. Then, a solution of potassium cyanide (0.58 g)in water (5 ml) is added thereto, and the whole is further stirred forfour hours. The reaction mixture is extracted with ethyl acetate, andthe extract is washed with saturated brine. The extract is dried overanhydrous magnesium sulfate and concentrated under reduced pressure togive the titled reference Compound (1.18 g).

[0193] The following compounds are obtained by a method similar toReference Example 3.

[0194] (2RS,3S)-3-(tert-Butoxycarbonyl)amino-2-hydroxy-5-methylhexanenitrile(Reference Compound No. 3-2)

[0195] IR(Film,cm⁻¹)3350, 2960, 2872, 2248, 1688, 1523, 1454, 1393

[0196] (2RS,3S)-3-(tert-Butoxycarbonyl)amino-4-(4-chlorophenyl)-2-hydroxybutanenitrile(Reference Compound No. 3-3)

[0197] mp 110-119.5° C.

[0198] IR(KBr,cm⁻¹)3499, 3381, 2955, 2932, 2253, 1684, 1512

[0199] (2RS,3S)-3-(tert-Butoxycarbonyl)amino-2-hydroxy-5-phenylpentanenitrile(Reference Compound No. 3-4)

[0200] mp 62.0-73.0° C.

[0201] IR(KBr,cm⁻¹)3499, 3381, 2955, 2932, 2253, 1684, 1512

[0202] (2RS,3S)-3-(Benzyloxycarbonyl)amino-2-hydroxy-4-phenylbutanenitrile(Reference Compound No. 3-5)

[0203] IR(Film,cm⁻¹)3331, 3063, 3030, 2949, 1706, 1604, 1585, 1517, 1454

Reference Example 4

[0204] Isopropyl (2RS, 3S)-3-amino-2-hydroxy-4-phenylbutyrate (ReferenceCompound No. 4-1)

[0205] A solution of (2RS,3S)-3-(tert-butoxycarbonyl)amino-2-hydroxy-4-phenylbutanenitrile (1.00g, Reference compound No. 3-1) in isopropanol (40 ml) is saturated withhydrogen chloride under ice cooling, then the temperature is raised toroom temperature, and the solution is stirred overnight. The reactionmixture is concentrated under reduced pressure, 0.1 N hydrochloric acidis added to the resulting residue, and the whole is stirred at roomtemperature for 20 minutes. The reaction mixture is washed with diethylether, a saturated aqueous sodium hydrogencarbonate solution is added tothe reaction mixture to basify the system, and the whole is extractedwith ethyl acetate. The extract is washed with water and saturated brinesuccessively and dried over anhydrous magnesium sulfate. The extract isconcentrated under reduced pressure to give the titled referenceCompound (0.54 g).

[0206] The following compounds are obtained by a method similar toReference Example 4.

[0207] Isopropyl (2RS, 3S)-3-amino-2-hydroxy-5-methylhexanoate(Reference Compound No. 4-2)

[0208] IR(Film,cm⁻¹)3360, 3298, 2956, 2870, 1733, 1590, 1468, 1386

[0209] Isopropyl (2RS, 3S)-3-amino-4-(4-chlorophenyl)-2-hydroxybutyrate(Reference Compound No. 4-3)

[0210] IR(KBr,cm⁻¹)3360, 3302, 2983, 2836, 1732, 1594, 1491, 1229, 1207

[0211] Isopropyl (2RS, 3S)-3-amino-2-hydroxy-5-phenylvalerate (ReferenceCompound No. 4-4)

[0212] IR(Film,cm⁻¹)3499, 3381, 2955, 2932, 2253, 1684, 1512

Reference Example 5

[0213] Benzyl (2RS, 3S)-3-amino-2-hydroxy-4-phenylbutyratep-toluenesulfonate (Reference Compound No. 5-1)

[0214] A solution of isopropyl (2RS,3S)-3-amino-2-hydroxy-4-phenylbutyrate (1.42 g, Reference Compound No.4-1), p-toluenesulfonic acid monohydrate (1.37 g) and benzyl alcohol (6ml) in benzene (20 ml) is subjected to azeotropic distillation overnightwith a Dean-Stark apparatus, and water and isopropanol are separated.Diethyl ether is added to the reaction mixture, and precipitatedcrystals are filtered off to give the titled reference Compound (1.68g).

[0215] mp 135.0-150.0° C.

[0216] IR(KBr,cm⁻¹)3335, 2923, 1742, 1631, 1499, 1172, 1125, 1037, 1012,815, 699,

Reference Example 6

[0217] (2S)-2-(tert-Butoxycarbonyl)amino-3-(4-chlorophenyl)propionicAcid (Reference Compound No. 6-1)

[0218] Triethylamine (1.05 ml) is added to a suspension ofp-chlorophenylalanine (1.00 g) in water (5 ml). Then, a solution ofdi-tert-butyl dicarbonate (1.20 g) in tetrahydrofuran (5 ml) is added tothe mixture, and the whole is stirred for three hours. The reactionmixture is concentrated under reduced pressure, an aqueous citric acidsolution is added to the resulting residue, and the whole is extractedwith ethyl acetate. The extract is washed with water and saturated brinesuccessively and dried over anhydrous magnesium sulfate. The extract isconcentrated under reduced pressure to give the titled referenceCompound (1.47 g).

[0219] mp 108.9-112.4° C.

[0220] [α]_(D) ²⁰ +12.7° (c=1.0, methanol)

[0221] IR(KBr,cm⁻¹)3347, 2990, 2930, 1713, 1689, 1522

[0222] The following compound is obtained by a method similar toReference Example 6.

[0223] (2S)-2-(tert-Butoxycarbonyl)amino-4-phenylbutyric Acid (ReferenceCompound No. 6-2)

[0224] [α]_(D) ²⁰ +31.50 (c=0.54, chloroform)

[0225] IR(Film,cm⁻¹)3322, 2978, 1716, 1497, 1455, 1368

Reference Example 7

[0226]N¹-Methyl-N¹-methoxy-(2S)-2-(tert-butoxycarbonyl)amino-3-(4-chlorophenyl)propionamide(Reference Compound No. 7-1)

[0227] Carbonyldiimidazole (876 mg) is added to a solution of(2S)-2-(tert-butoxycarbonyl)amino-3-(4-chlorophenyl)propionic acid (1.35g, Reference Compound No. 6-1) in tetrahydrofuran (10 ml), and themixture is stirred for 30 minutes. To the mixture is added a solution ofN, O-dimethylhydroxylamine hydrochloride (483 mg) anddiisopropylethylamine (941 μl) in dimethylformamide (5 ml), and thewhole is stirred for three days. Ethyl acetate is added to the reactionmixture, and the whole is washed with water, 1 N hydrochloric acid,saturated aqueous sodium hydrogencarbonate solution and saturated brinesuccessively. The organic layer is dried over anhydrous magnesiumsulfate and concentrated under reduced pressure to give the titledreference Compound (1.53 g).

[0228] mp 59.5-61.1° C.

[0229] [α]_(D) ²⁰ +2.6° (c=1.0, methanol)

[0230] IR(KBr,cm⁻¹)3352, 2983, 1703, 1652, 1510

[0231] The following compound is obtained by a method similar toReference Example 7.

[0232]N¹-Methyl-N¹-methoxy-(2S)-2-(tert-butoxycarbonyl)amino-4-phenylbutyramide(Reference Compound No. 7-2)

[0233] [α]_(D) ²⁰ +35.90 (c=1.0, methanol)

[0234] IR(Film, cm⁻¹)3324, 2976, 2934, 1712, 1662, 1497

Reference Example 8

[0235] (2S)-2-(tert-Butoxycarbonyl)amino-3-(4-chlorophenyl)propanal(Reference Compound No. 8-1)

[0236] A suspension of lithium aluminum hydride (183 mg) in diethylether (7.5 ml) is cooled to −15° C., and a solution ofN¹-methyl-N¹-methoxy-(2S)-2-(tert-butoxycarbonyl)amino-3-(4-chlorophenyl)propionamide(1.5 g Reference compound No. 7-1) in diethyl ether (7.5 ml) is added tothe suspension. The temperature is raised to −5° C., and the mixture isstirred for 30 minutes. Ethyl acetate (4 ml) is added to the reactionmixture, the whole is stirred for five minutes, and a 5% aqueouspotassium hydrogensulfite solution (10 ml) is added thereto. Ethylacetate is added to the reaction mixture, and the whole is washed with 1N hydrochloric acid, water, a saturated aqueous sodium hydrogencarbonatesolution and saturated brine successively and dried over anhydrousmagnesium sulfate. The organic layer is concentrated under reducedpressure to give the titled reference compound (1.16 g).

[0237] mp 117.3-120.5° C.

[0238] [α]_(D) ²⁰ −35.3° (c=1.0, methanol)

[0239] IR(KBr,cm⁻¹)3366, 2984, 2737, 1731, 1688, 1517

[0240] The following compound is obtained by a method similar toReference Example 8.

[0241] (2S)-2-tert-Butoxycarbonylamino-4-phenylbutanal (ReferenceCompound No. 8-2)

[0242] [α]_(D) ²⁰ +15.5° (c=1.0, methanol)

[0243] IR(Film,cm⁻¹)3350, 2977, 2930, 1698, 1497

Reference Example 9

[0244] (1RS,2S)-1-(2-Benzothiazolyl)-2-(tert-butoxycarbonyl)amino-3phenyl-1-propanol(Reference Compound No. 9-1)

[0245] A solution of benzothiazole (0.74 g) in tetrahydrofuran (10 ml)is cooled with dry ice/methanol under a nitrogen atmosphere. A 1.6 Mn-butyllithium/hexane solution (3.5 ml) is added dropwise thereto, andthe mixture is stirred for 30 minutes. A solution of(2S)-2-(tert-butoxycarbonyl)amino-3-phenyl-1-propanal (1.25 g, ReferenceCompound No. 2-1) in tetrahydrofuran (10 ml) is added to the mixture,and the whole is further stirred for four hours. A saturated aqueousammonium chloride solution is added to the reaction mixture, thetemperature is raised to room temperature, and the whole is stirred for30 minutes. The reaction mixture is extracted with ethyl acetate, andthe extract is washed with water and saturated brine successively anddried over anhydrous magnesium sulfate. The extract is concentratedunder reduced pressure, and the resulting residue is purified by silicagel column chromatography to give the titled reference Compound (0.93g).

[0246] IR(KBr,cm⁻¹)3338, 1691, 1497, 1392, 1367, 1168, 759, 700

[0247] The following compounds are obtained by a method similar toReference Example 9.

[0248] (1RS,2S)-2-(tert-Butoxycarbonyl)amino-3-phenyl-1-(2-thiazolyl)-1-propanol(Reference Compound No. 9-2)

[0249] (1RS,2S)-1-(2-Benzoxazolyl)-2-(tert-butoxycarbonyl)amino-3-phenyl-1-propanol(Reference Compound No. 9-3)

[0250] (1RS,2S)-2-(tert-Butoxycarbonyl)amino-1-(2-oxazolyl)-3-phenyl-1-propanol(Reference Compound No. 9-4)

Reference Example 10

[0251] (1RS, 2S)-2-Amino-1-(2-benzothiazolyl)-3-phenyl-1-propanolhydrochloride (Reference Compound No. 10-1)

[0252] A 4 N hydrogen chloride/dioxane solution (6.3 ml) is added to(1RS,2S)-1-(2-benzothiazolyl)-2-(tert-butoxycarbonyl)amino-3-phenyl-1-propanol(0.64 g, Reference Compound No. 9-1) under ice cooling, then thetemperature is raised to room temperature, and the mixture is stirredfor 30 minutes. The reaction mixture is concentrated under reducedpressure, diethyl ether is added to the residue, and precipitatedcrystals are filtered off to give the titled reference Compound (0.56g).

[0253] IR(KBr,cm⁻¹)2857, 1600, 1495, 1454, 1117, 1067, 759, 700

[0254] The following compounds are obtained by a method similar toReference Example 10.

[0255] (1RS, 2S)-2-Amino-3-phenyl-1-(2-thiazolyl)-1-propanolhydrochloride (Reference Compound No. 10-2)

[0256] (1RS, 2S)-2-Amino-1-(2-benzoxazolyl)-3-phenyl-1-propanolhydrochloride (Reference Compound No. 10-3)

[0257] (1RS, 2S)-2-Amino-1-(2-oxazolyl)-3-phenyl-1-propanolhydrochloride (Reference Compound No. 10-4)

Reference Example 11

[0258] (1RS,2S)-2-(Benzyloxycarbonyl)amino-1-(4,5-dihydro-1,3-thiazol-2-yl)-3-phenyl-1-propanol(Reference Compound No. 11-1)

[0259] Acetyl chloride (7.8 ml) is added to a solution of ethanol (7.60ml) in methylene chloride (20 ml) under ice cooling, and the mixture isstirred for 15 minutes. A solution of (2RS,3S)-3-(benzyloxycarbonyl)amino-2-hydroxy-4-phenylbutanenitrile (2.00 g,Reference Compound No. 3-5) in methylene chloride (10 ml) is added tothe mixture, and the whole is stirred overnight. The reaction mixture isconcentrated under reduced pressure, and methylene chloride (30 ml) isadded to the resulting residue. This solution is cooled with ice,triethylamine (3.60 ml) is added to the solution, and the mixture isstirred for 10 minutes. 2-Aminoethanethiol hydrochloride (1.46 g) isadded to the mixture, then the temperature is raised to roomtemperature, and the whole is stirred overnight. Ethyl acetate is addedto the reaction mixture, the whole is washed with a 10% aqueous citricacid solution, saturated brine, a saturated aqueous sodiumhydrogencarbonate solution and saturated brine successively, and theorganic layer is dried over anhydrous magnesium sulfate. The organiclayer is concentrated under reduced pressure, and the resulting residueis purified by silica gel column chromatography to give the titledreference Compound (1.70 g).

[0260] IR(Film,cm⁻¹)3328, 3062, 3029, 2942, 1703, 1620, 1585, 1497, 1454

[0261] The following compounds are obtained by a method similar toReference Example 11.

[0262] (1RS,2S)-2-(Benzyloxycarbonyl)amino-1-(4,5-dihydro-1,3-oxazol-2-yl)-3-phenyl-1-propanol(Reference Compound No. 11-2)

[0263] IR(Film,cm⁻¹)3318, 3062, 3028, 2972, 1706, 1670, 1585, 1496, 1454

[0264] (1RS,2S)-2-(Benzyloxycarbonyl)amino-1-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-3-phenyl-1-propanol(Reference Compound No. 11-3)

[0265] (1RS,2S)-2-(Benzyloxycarbonyl)amino-1-(3-oxa-1-azaspiro[4.4]non-1-en-2-yl)-3-phenyl-1-propanol(Reference Compound No. 11-4)

[0266] IR(Film,cm⁻¹)3321, 3029, 2957, 1715, 1667, 1604, 1504, 1454

[0267] (1RS,2S)-2-(Benzyloxycarbonyl)amino-1-(5,5-dimethyl-4,5-dihydro-1,3-thiazol-2-yl)-3-phenyl-1-propanol(Reference Compound No. 11-5)

[0268] IR(Film,cm⁻¹)3330, 3063, 3030, 2958, 2927, 1714, 1614, 1514, 1454

Reference Example 12

[0269] (1RS,2S)-2-Amino-1-(4,5-dihydro-1,3-thiazol-2-yl)-3-phenyl-1-propanol(Reference Compound No. 12-1)

[0270] Iodotrimethylsilane (10 ml) is added to a solution of (1RS,2S)-2(benzyloxycarbonyl)amino-1-(4,5-dihydro-1,3-thiazol-2-yl)-3-phenyl-1-propanol(650 mg, Reference Compound No. 11-1) in acetonitrile (10 ml), and themixture is stirred for 30 minutes. The reaction mixture is concentratedunder reduced pressure, ethyl acetate is added to the resulting residue,and the whole is extracted with 1 N hydrochloric acid. Sodiumhydrogencarbonate is added to the extract to basify the system, and thewhole is extracted with ethyl acetate. The extract is washed withsaturated brine and dried over anhydrous magnesium sulfate. The extractis concentrated under reduced pressure to give the titled referenceCompound (323 mg).

[0271] mp 82.3-90.0° C.

[0272] IR(Film,cm⁻¹)3320, 3024, 2916, 1649, 1578, 1542, 1495, 1453

[0273] The following compounds are obtained by a method similar toReference Example 12.

[0274] (1RS,2S)-2-Amino-1-(4,5-dihydro-1,3-oxazol-2-yl)-3-phenyl-1-propanol(Reference Compound No. 12-2)

[0275] IR(Film,cm⁻¹)3400-2900, 1620, 1528, 1495, 1451

[0276] (1RS,2S)-2-Amino-1-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-3-phenyl-1-propanol(Reference Compound No. 12-3)

[0277] (1RS,2S)-2-(Benzyloxycarbonyl)amino-1-(3-oxa-1-azaspiro[4.4]non-1-en-2-yl)-3-phenyl-1-propanol(Reference Compound No. 12-4)

[0278] IR(Film,cm⁻¹)3286, 2955, 1659, 1603, 1524, 1496, 1454

[0279] (1RS,2S)-2-(Benzyloxycarbonyl)amino-1-(5,5-dimethyl-4,5-dihydro-1,3-thiazol-2-yl)-3-phenyl-1-propanol(Reference Compound No. 12-5)

[0280] IR(KBr,cm⁻¹)3350, 3280, 3028, 2922, 1612, 1559, 1496, 1456

Reference Example 13

[0281] Isopropyl (2RS,3S)-3-(benzyloxycarbonyl)amino-2-hydroxy-4-phenylbutyrate (ReferenceCompound No. 13-1)

[0282] Water (10 ml) and sodium carbonate (763 mg) are added to asolution of isopropyl (2RS, 3S)-3-amino-2-hydroxy-4-phenylbutyrate (800mg, Reference Compound No. 4-1) in diethyl ether (10 ml). Benzylchloroformate (691 mg) is added to the mixture, and the whole is stirredfor two hours. Ethyl acetate is added to the reaction mixture, and thewhole is washed with a saturated aqueous sodium hydrogencarbonatesolution, water and saturated brine successively and dried overanhydrous magnesium sulfate. The organic layer is concentrated underreduced pressure, and the resulting residue is purified by silica gelcolumn chromatography to give the titled reference Compound (1.02 g).

[0283] IR(Film,cm⁻¹)3360, 2981, 1726, 1520

Reference Example 14

[0284] (2RS, 3S)-3-(Benzyloxycarbonyl)amino-4-phenyl-1,2-butanediol(Reference Compound No. 14-1)

[0285] Ethanol (1 ml) and lithium bromide (36.7 mg) are added to asolution of isopropyl (2RS,3S)-3-(benzyloxycarbonyl)amino-2-hydroxy-4-phenylbutyrate (150 mg,Reference Compound No. 13-1) in tetrahydrofuran (1 ml). The mixture iscooled with ice, sodium borohydride (42.1 mg) is added to the mixture,and the temperature is raised to room temperature. The whole is stirredovernight, water is added thereto, and the whole is further stirred forone hour. The reaction mixture is concentrated under reduced pressure,and the resulting residue is extracted with ethyl acetate. The extractis washed with saturated brine and dried over anhydrous magnesiumsulfate. The extract is concentrated under reduced pressure to give thetitled reference Compound (105 mg).

[0286] IR(KBr,cm⁻¹)3362, 3214, 2933, 2889, 1694, 1604, 1525

Reference Example 15

[0287] (2RS,3S)-3-(Benzyloxycarbonyl)amino-1-(tert-butyldimethylsilyl)oxy-4-phenyl-2-butanol(Reference Compound No. 15-1)

[0288] Thethylamine (69 μl) and 4-dimethylaminopyridine (catalyticamount) are added to a solution of (2RS,3S)-3-(benzyloxycarbonyl)amino-4-phenyl-1,2-butanediol (130 mg,Reference Compound No. 14-1) in methylene chloride (2 ml).tert-Butyldimethylsilyl chloride (68.3 mg) is added to the mixture, andthe whole is stirred overnight. Ethyl acetate is added to the reactionmixture, the whole is washed with water and saturated brinesuccessively, and the organic layer is dried over anhydrous magnesiumsulfate. The organic layer is concentrated under reduced pressure, andthe resulting residue is purified by silica gel column chromatography togive the titled reference Compound (149 mg).

[0289] IR(Film,cm⁻¹)3430, 2929, 2857, 1701, 1497

Reference Example 16

[0290] (2RS,3S)-3-Amino-1-(tert-butyldimethylsilyl)oxy-4-phenyl-2-butanol (ReferenceCompound No. 16-1)

[0291] 5% Palladium-carbon (130 mg) is added to a solution of (2RS,3S)-3-(benzyloxycarbonyl)amino-1-(tert-butyldimethylsilyl)oxy-4-phenyl-2-butanol(130 mg, Reference Compound No. 15-1) in methanol (5 ml), and themixture is stirred under a hydrogen atmosphere (1 atm) for three hours.The reaction mixture is filtered to remove the catalyst. The filtrate isconcentrated under reduced pressure to give the titled referenceCompound (89.2 mg).

[0292] IR(Film,cm⁻¹)3433, 2928, 2884, 2857, 1698, 1497

Reference Example 17

[0293] (2RS, 3S)-3-Amino-2-hydroxy-4-phenylbutyramide (ReferenceCompound No. 17-1)

[0294] A solution of isopropyl (2RS,3S)-3-amino-2-hydroxy-4-phenylbutyrate (200 mg, Reference Compound No.4-1) in methanol (3 ml) is saturated with an ammonia gas, and thesolution is sealed and stirred overnight. The reaction solution isconcentrated under reduced pressure to give the titled referenceCompound (162 mg).

[0295] IR(KBr,cm⁻¹)3395, 3269, 2909, 1668, 1619, 1600, 1584

Reference Example 18

[0296] Isopropyl (2RS,3S)-3-(tert-butoxycarbonyl)amino-2-hydroxy-4-phenylbutyrate (ReferenceCompound No. 18-1)

[0297] A solution of di-tert-butyl dicarbonate (101 mg) intetrahydrofuran (1 ml) is added to a solution of isopropyl (2RS,3S)-3-amino-2-hydroxy-4-phenylbutyrate (100 mg, Reference Compound No.4-1) in tetrahydrofuran (1 ml), and the mixture is stirred for 3.5hours. The reaction mixture is concentrated under reduced pressure, andthe resulting residue is purified by silica gel column chromatography togive the titled reference Compound (121 mg).

[0298] IR(Film,cm⁻¹)3381, 2979, 2933, 1716, 1604, 1497

Reference Example 19

[0299] (2RS, 3S)-3-(tert-Butoxycarbonyl)amino-2-hydroxy-4-phenylbutyricacid (Reference Compound No. 19-1)

[0300] A 1 N aqueous lithium hydroxide solution (4 ml) is added to asolution of isopropyl (2RS,3S)-(tert-butoxycarbonyl)amino-2-hydroxy-4-phenylbutyrate (950 mg) inmethanol (10 ml), and the mixture is stirred for three hours. Thereaction mixture is washed with diethyl ether, 1 N hydrochloric acid isadded to the mixture to acidify the system, and the whole is extractedwith ethyl acetate. The extract is washed with saturated brine and driedover anhydrous magnesium sulfate. The extract is concentrated underreduced pressure to give the titled reference Compound (801 mg).

Reference Example 20

[0301] N¹-Isopropyl-(2RS,3S)-3-(tert-butoxycarbonyl)amino-2-hydroxy-4-phenylbutyramide (ReferenceCompound No. 20-1)

[0302] N-Methylmorpholine (200 μl) is added to a solution of (2RS,3S)-(tert-butoxycarbonyl)amino-2-hydroxy-4-phenylbutyric acid (440 mg,Reference Compound No. 19-1) in tetrahydrofuran (5 ml), and the mixtureis cooled to −10° C. Isobutyl chloroformate (230 μl) is added to themixture, and the whole is stirred for 20 minutes. Further, a solution ofisopropylamine and N-methylmorpholine (200 μl) in tetrahydrofuran (5 ml)is added thereto, and the whole is stirred for two hours. Ethyl acetateis added to the reaction mixture, the whole is washed with water andsaturated brine successively, and the organic layer is dried overanhydrous magnesium sulfate. The organic layer is concentrated underreduced pressure, and the resulting residue is washed with diisopropylether to give the titled reference Compound (329 mg).

[0303] mp 126.0-145.0° C.

[0304] IR(KBr,cm⁻¹)3444, 3310, 2979, 1705, 1678, 1634, 1526, 1496

[0305] The following compound is obtained by a method similar toReference Example 20.

[0306] N¹, N¹-Dimethyl-(2RS,3S)-3-(tert-butoxycarbonyl)amino-2-hydroxy-4-phenylbutyramide (ReferenceCompound No. 20-2)

Reference Example 21

[0307] N¹-Isopropyl-(2RS, 3S)-3-amino-2-hydroxy-4-phenylbutyramide(Reference Compound No. 21-1)

[0308] A 4 M hydrogen chloride/ethyl acetate solution (2 ml) is added toN¹-isopropyl-(2RS,3S)-3-(tert-butoxycarbonylamino)-2-hydroxy-4-phenylbutyramide (300 mg,Reference Compound No. 20-1), and the mixture is stirred for five hours.The reaction mixture is concentrated under reduced pressure, a saturatedaqueous sodium hydrogencarbonate solution is added to the resultingresidue, and the whole is extracted with ethyl acetate. The extract iswashed with water and saturated brine successively and dried overanhydrous magnesium sulfate. The extract is concentrated under reducedpressure to give the titled reference Compound (212 mg).

[0309] The following compound is obtained by a method similar toReference Example 21.

[0310] N¹, N¹-Dimethyl-(2RS, 3S)-3-amino-2-hydroxy-4-phenylbutyramide(Reference Compound No. 21-2)

Reference Example 22

[0311] N¹-Methoxy-(2S)-2-(tert-butoxycarbonyl)amino-3-phenylpropionamide(Reference Compound No. 22-1)

[0312] N-Methylmorpholine (0.54 ml), 1-hydroxybenzotriazole (611 mg) andO-methylhydroxylamine hydrochloride (350 mg) are added to a solution of(2S)-2-(tert-butoxycarbonyl)amino-3-phenyl-1-propionic acid (1.00 g) inmethylene chloride (7.5 ml). The mixture is cooled with ice, and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (867 mg) isadded to the mixture. The temperature is raised to room temperature, andthe whole is stirred overnight. Ethyl acetate is added to the reactionmixture, the whole is washed with a 0.1 N aqueous sodium hydroxidesolution, 1 N hydrochloric acid and saturated brine successively, andthe organic layer is dried over anhydrous magnesium sulfate. The organiclayer is concentrated under reduced pressure to give the titledreference Compound (1.11 g).

[0313] [α]_(D) ²⁰ −6.2° (c=1.0, methanol)

[0314] IR(KBr,cm⁻¹)3334, 3241, 1667, 1522

[0315] The following compounds are obtained by a method similar toReference Example 22.

[0316]N¹-Methoxy-N¹-methyl-(2S)-2-(tert-butoxycarbonyl)amino-3-phenylpropionamide(Reference Compound No. 22-2)

[0317] [α]_(D) ²⁰ +4.30 (c=1.0, methanol)

[0318] IR(Film,cm⁻¹)3323, 1712, 1662, 1496

[0319](2S)-2-(tert-Butoxycarbonyl)amino-1-morpholino-3-phenyl-1-propanone(Reference Compound No. 22-3)

[0320] [α]_(D) ²⁰ +9.0° (c=1.0, methanol)

[0321] IR(Film,cm⁻¹)3306, 2975, 2929, 2859, 1708, 1640, 1495, 1454, 1391

[0322](2S)-2-(tert-Butoxycarbonyl)amino-3-phenyl-1-piperidino-1-propanone(Reference Compound No. 22-4)

[0323] [α]_(D) ²⁰ +1.8° (c=0.99, methanol)

[0324] IR(Film,cm⁻¹)3293, 2975, 2936, 1708, 1632, 1494

[0325](2S)-1-1{(2S)-2-(Aminocarbonyl)pyrrolidin-1-yl}-2-(tert-butoxycarbonyl)amino-3-phenyl-1-propanone(Reference Compound No. 22-5)

[0326] IR(Film,cm⁻¹)3318, 1692, 1641, 1445, 1168, 752

Reference Example 23

[0327] N¹-Methoxy-(2S)-2-amino-3-phenylpropionamide hydrogentrifluoroacetate (Reference Compound No. 23-1)

[0328] Trifluoroacetic acid (4.0 ml) is added toN¹-methoxy-(2S)-2-(tert-butoxycarbonyl)amino-3-phenylpropionamide (600mg, Reference compound No. 22-1), and the mixture is stirred for 10minutes. The reaction mixture is concentrated under reduced pressure,ethyl acetate is added to the resulting residue, and the whole isextracted with 1 N hydrochloric acid. A saturated sodiumhydrogencarbonate solution is added to the extract to basify the system,and the whole is extracted with ethyl acetate. The extract is washedwith saturated brine and dried over anhydrous magnesium sulfate. Theextract is concentrated under reduced pressure to give the titledreference Compound (70.8 mg).

[0329] The following compound is obtained by a method similar toReference Example 23.

[0330] N¹-Methoxy-N¹-methyl-(2S)-2-amino-3-phenyl-1-propionamidehydrogen trifluoroacetate (Reference Compound No. 23-2)

Reference Example 24

[0331] (2S)-2-Amino-1-morpholino-3-phenyl-1-propanone hydrochloride(Reference Compound No. 24-1)

[0332] A 4 N hydrogen chloride/ethyl acetate solution (7 ml) is added toa solution of(2S)-2-(tert-butoxycarbonyl)amino-1-morpholino-3-phenyl-1-propanone(3.10 g, Reference compound No. 22-3) in ethyl acetate (7 ml), and themixture is stirred for four hours. The reaction mixture is concentratedunder reduced pressure to give the titled reference compound (2.36 g).

[0333] mp 232.4-236.6° C.

[0334] [α]_(D) ²⁰ +63.9° (c=1.00, methanol)

[0335] IR(Film,cm⁻¹)3050, 2856, 1659, 1597, 1573, 1506, 1468, 1453, 1442

[0336] The following compounds are obtained by a method similar toReference Example 24.

[0337] (2S)-2-Amino-3-phenyl-1-piperidino-1-propanone hydrogentrifluoroacetate (Reference Compound No. 24-2)

[0338] mp 149-154° C.

[0339] [α]_(D) ²⁰ +54.40 (c=1.00, methanol)

[0340] IR(Film,cm⁻¹)3050, 2856, 1659, 1597, 1573, 1506, 1468, 1453, 1442

[0341](2S)-2-Amino-1-{(2S)-2-(aminocarbonyl)pyrrolidin-1-yl}-3-phenylpropanonehydrochloride (Reference compound No. 24-3)

[0342] mp 120° C.

[0343] [α]_(D) ²⁰ −13.9° (c=1.00, methanol)

[0344] IR(KBr,cm⁻¹)3700-2500, 1653, 1497

Reference Example 25

[0345](2S)-2-(Benzyloxycarbonyl)amino-1-{4-(tert-butoxycarbonyl)piperazin-1-yl}-3-phenyl-1-propanone(Reference Compound No. 25-1)

[0346] N-Methylmorpholine (1.3 ml), hydroxybenzotriazole (2.03 g) andtert-butyl piperazinecarboxylate (2.24 ml) are added to a solution of(2S)-2-(benzyloxycarbonyl)amino-3-phenyl-1-propionic acid (2.99 g) inmethylene chloride (30 ml). The mixture is cooled with ice,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.30 g) isadded to the mixture, and the whole is stirred overnight. Ethyl acetateis added to the reaction mixture, the whole is washed with a 0.1 Naqueous sodium hydroxide solution, 0.1 N hydrochloric acid and saturatedbrine successively, and the organic layer is dried over anhydrousmagnesium sulfate. The organic layer is concentrated under reducedpressure to give the titled reference Compound (4.68 g).

[0347] [α]_(D) ²⁰ +14.4° (c=1.00, methanol)

[0348] IR(Film,cm⁻¹)3292, 3007, 2976, 2930, 1699, 1640, 1529, 1497

Reference Example 26

[0349](2S)-2-Amino-1-{4-(tert-butoxycarbonyl)piperazin-1-yl}-3-phenyl-1-propanone(Reference Compound No. 26-1)

[0350] A solution of(2S)-2-(benzyloxycarbonyl)amino-1-{4-(tert-butoxycarbonyl)piperazin-1-yl}-3-phenyl-1-propanone(4.2 g, Reference Compound No. 25-1) in ethanol (30 ml) is saturatedwith a nitrogen gas. Then, 5% palladium hydroxide/carbon (2.1 g) isadded to the solution, and the whole is stirred overnight under ahydrogen atmosphere (4.2 kgf/cm⁻¹). The reaction mixture is filtered toremove the catalyst. The filtrate is concentrated under reducedpressure, ethyl acetate is added to the resulting residue, and the wholeis extracted with a 10% aqueous citric acid solution. Sodiumhydrogencarbonate is added to the extract to basify the system, and thewhole is extracted with ethyl acetate. The extract is dried overanhydrous magnesium sulfate and concentrated under reduced pressure togive the titled reference Compound (1.32 g).

[0351] IR(KBr,cm⁻¹)3367, 1694, 1641, 1454, 1419

Reference Example 27

[0352] (2S)-2-(tert-Butoxycarbonyl)amino-1,3-diphenyl-1-propanone(Reference Compound No. 27-1)

[0353] A solution ofN¹-methoxy-N¹-methyl-(2S)-2-(tert-butoxycarbonyl)amino-3-phenylpropionamide(700 mg, Reference Compound No. 22-2) in anhydrous tetrahydrofuran (10ml) is cooled to −78° C., a 1.8 N phenyllithium/cydohexane/ethersolution (6.31 ml) is added thereto, and the mixture is stirred for twohours. A saturated aqueous ammonium chloride solution (20 ml) is addedto the reaction mixture, and the whole is extracted with ethyl acetate.The extract is washed with saturated brine and dried over anhydrousmagnesium sulfate. The extract is concentrated under reduced pressure,and the resulting residue is purified by silica gel columnchromatography to give the titled reference Compound (425 mg).

[0354] mp 109.0-110.0° C.

[0355] [α]_(D) ²⁰ +15.6° (c=1.0, methanol)

[0356] IR(KBr,cm⁻¹)3353, 3325, 1685, 1597, 1530

Reference Example 28

[0357] (2S)-2-Amino-1,3-diphenyl-1-propanone hydrochloride (ReferenceCompound No. 28-1)

[0358] A 4 N hydrogen chloride/ethyl acetate solution (8 ml) is added toa solution of (2S)-2-(tert-butoxycarbonyl)amino-1,3-diphenylpropanone(300 mg, Reference Compound No. 27-1) in ethyl acetate (10 ml), and themixture is stirred for three hours. The reaction mixture is concentratedunder reduced pressure, and the resulting residue is washed with hexaneto give the titled reference Compound (224 mg).

[0359] mp 215.0-226.0° C.

[0360] [α]_(D) ²⁰ +72.4° (c=1.0, methanol)

[0361] IR(KBr,cm⁻¹)3065, 2820, 1690, 1594, 1497

Reference Example 29

[0362] (4RS)-2-Phenyl-4-phenylmethyl-5(4H)-oxazolone (Reference CompoundNo. 29-1)

[0363] A suspension of N-benzoyl-DL-phenylalanine (5.39 g) and aceticanhydride (12.3 g) is stirred at 80° C. for 40 minutes under a nitrogenatmosphere. The reaction mixture is concentrated under reduced pressureto give the titled reference compound (4.30 g).

[0364] mp 70.0-72.0° C.

[0365] IR(KBr,cm⁻¹)1826, 1813, 1647, 1297, 1079, 1048, 902, 695

Reference Example 30

[0366] (3RS)-3-Benzoylamino-2-oxo-4-phenyl-1,1,1-trifluorobutane(Reference Compound No. 30-1)

[0367] A solution of (4RS)-2-phenyl-4-phenylmethyl-5(4H)-oxazolone (3.65g, Reference compound No. 29-1) in trifluoroacetic anhydride (6.13 g) isstirred for one day under a nitrogen atmosphere. The solution isconcentrated under reduced pressure, and oxalic acid (1.97 g) is addedto the resulting residue. The mixture is heated at 120° C. and stirredfor 30 minutes. The reaction mixture is cooled with ice, water is addedto the mixture, and the whole is extracted with ethyl acetate. Theextract is washed with water, a saturated aqueous sodiumhydrogencarbonate solution and saturated brine successively and driedover anhydrous magnesium sulfate. The extract is concentrated underreduced pressure to give the titled reference Compound (3.23 g).

[0368] mp 148.5-157.0° C.

[0369] IR(KBr,cm⁻¹)3344, 1763, 1654, 1624, 1554, 1166, 1110, 695

[0370] The following compound is obtained by a method similar toReference Example 30.

[0371](2RS)-2-Benzoylamino-4,4,5,5,6,6,6-heptafluoro-3-oxo-1-phenylhexane(Reference Compound No. 30-2)

[0372] mp 120.0-125.0° C.

[0373] IR(KBr,cm⁻¹)3292, 3031, 2908, 1753, 1723, 1653, 1580, 1525, 1491,1445, 1347

Reference Example 31

[0374] (2RS,3RS)-3-Benzoylamino-2-hydroxy-4-phenyl-1,1,1-trifluorobutane (ReferenceCompound No. 31-1)

[0375] Sodium borohydride (0.37 g) is added to a solution of(3RS)-3-benzoylamino-2-oxo-4-phenyl-1,1,1-trifluorobutane (3.12 g,Reference compound No. 30-1) in ethanol (25 ml), and the mixture isstirred at 35° C. for four hours. The reaction mixture is cooled withice, 6 N hydrochloric acid is added to the mixture, and the whole isextracted with ethyl acetate. The extract is washed with water, asaturated aqueous sodium hydrogencarbonate solution and saturated brinesuccessively and dried over anhydrous magnesium sulfate. The extract isconcentrated under reduced pressure to give the titled referencecompound (3.00 g).

[0376] mp 176.0-183.0° C.

[0377] IR(KBr,cm⁻¹)3309, 1646, 1538, 1237, 1261, 1190, 1133, 699

[0378] The following compound is obtained by a method similar toReference Example 31.

[0379] (2RS,3RS)-2-Benzoylamino-4,4,5,5,6,6,6-heptafluoro-3-hydroxy-1-phenylhexane(Reference Compound No. 31-2)

[0380] mp 152.0-160.0° C.

[0381] IR(KBr,cm⁻¹)3216, 3065, 3030, 2931, 1644, 1576, 1538, 1494, 1454,1356

Reference Example 32

[0382] (2RS, 3RS)-3-Amino-2-hydroxy-4-phenyl-1,1,1-trifluorobutanehydrochloride (Reference Compound No. 32-1)

[0383] 12 N Hydrochloric acid is added to a suspension of (2RS,3RS)-3-benzoylamino-2-hydroxy-4-phenyl-1,1,1-trifluorobutane (3.00 g,Reference Compound No. 31-1), ethanol (60 ml) and water (60 ml), and themixture is refluxed for one day. After standing, the reaction mixture isconcentrated under reduced pressure, diethyl ether is added to theresulting residue, and the whole is extracted with water. The extract isconcentrated under reduced pressure to give the titled referenceCompound (1.58 g).

[0384] mp 218.0-226.0° C.

[0385] IR(KBr,cm⁻¹)3318, 3128, 2924, 1601, 1513, 1285, 1181, 1156

Reference Example 33

[0386] (2RS,3RS)-2-Amino-4,4,5,5,6,6,6-heptafluoro-3-hydroxy-1-phenylhexane(Reference Compound No. 33-1)

[0387] Lithium aluminum hydride (118 mg) is added to a solution of (2RS,3RS)-2-benzoylamino-4,4,5,5,6,6,6-heptafluoro-3-hydroxy-1-phenylhexane(1.10 g, Reference compound No. 31-2) in anhydrous tetrahydrofuran (20ml), and the mixture is stirred for three days. The reaction mixture isfiltered through Celite to remove impurities. The filtrate isconcentrated under reduced pressure, diethyl ether is added to theresulting residue, and the whole is extracted with 0.1 N hydrochloricacid. Sodium hydrogencarbonate is added to the extract to basify thesystem, and the whole is extracted with ethyl acetate. The extract iswashed with saturated brine and dried over anhydrous magnesium sulfate.The extract is concentrated under reduced pressure to give the titledreference compound (164 mg).

[0388] IR(Film,cm⁻¹)3357, 3312, 3065, 2915, 2873, 1644, 1614, 1558,1540, 1496

[0389] The following Reference Examples 34 to 65 show examples of thesynthesis of the carboxylic acid derivatives [III] described in detailin the section of “Disclosure of the Invention”.

Reference Example 34

[0390] Ethyl 2-(2,2-diethoxyethylthio)acetate (Reference Compound No.34-1)

[0391] Sodium ethoxide (2.83 g) is added to a solution of ethylthioglycolate (5.00 g) and bromoacetaldehyde diethylacetal (8.20 g) inethanol (150 ml), and the mixture is refluxed for three hours. Thereaction mixture is allowed to stand at room temperature, water is addedto the mixture, and the whole is extracted with diethyl ether. Theextract is washed with saturated brine and dried over anhydrousmagnesium sulfate. The extract is concentrated under reduced pressure,and the resulting residue is purified by silica gel columnchromatography to give the titled reference Compound (5.75 g).

[0392] IR(Film,cm⁻¹)3439, 1735, 1478, 1445, 1273

Reference Example 35

[0393] Methyl 2-(2-hydroxybutylthio)acetate (Reference Compound No.35-1)

[0394] Sodium methoxide (1.94 g) is added to a solution of methylthioglycolate (3.18 g) in methanol (60 ml), and the mixture is stirredfor 10 minutes. Then, 2-butylene oxide (3.1 ml) is added to the mixture,and the whole is stirred overnight. The reaction mixture is concentratedunder reduced pressure, and the resulting residue is purified by silicagel column chromatography to give the titled reference compound (4.35g).

[0395] IR(Film,cm⁻¹)3437, 1735, 1437, 1284

Reference Example 36

[0396] Methyl 2-(2-oxobutylthio)acetate (Reference Compound No. 36-1)

[0397] Triethylamine (28.3 ml) is added to a solution of methyl2-(2-hydroxybutylthio)acetate (6.00 g, Reference Compound No. 35-1) indimethyl sulfoxide (180 ml). A sulfur trioxide-pyridine complex (20.0 g)is added to the mixture, and the whole is stirred for one hour. Water isadded to the reaction mixture, and the whole is stirred for 20 minutesand extracted with ethyl acetate. The extract is washed with water, 1 Nhydrochloric acid and saturated brine successively and dried overanhydrous magnesium sulfate. The extract is concentrated under reducedpressure, and the resulting residue is purified by silica gel columnchromatography to give the titled reference compound (5.93 g).

[0398] IR(Film,cm⁻¹)1736, 1710, 1588, 1436, 1410, 1351, 1280

Reference Example 37

[0399] Methyl 2-(2,2-dimethoxybutylthio)acetate (Reference Compound No.37-1)

[0400] Methyl orthoformate (10.8 ml) and p-toluenesulfonic acidmonohydrate. (catalytic amount) are added to a solution of methyl2-(2-oxobutylthio)acetate (5.80 g, Reference Compound No. 36-1) inmethanol (60 ml), and the mixture is refluxed for two hours. Thereaction mixture is cooled to 0° C., sodium methoxide (1.98 g) is addedto the mixture, and the whole is stirred for 20 minutes. The reactionmixture is concentrated under reduced pressure, ethyl acetate is addedto the resulting residue, and the whole is washed with saturated brine.The organic layer is dried over anhydrous magnesium sulfate, and thesolvent is distilled away under reduced pressure to give the titledreference Compound (6.85 g).

[0401] IR(Film,cm⁻¹)1735, 1458, 1436, 1344, 1281, 1197, 1156

Reference Example 38

[0402] 2-(2,2-Diethoxyethylthio)acetamide (Reference Compound No. 38-1)

[0403] An ammonia gas is bubbled through a solution of ethyl2-(2,2-diethoxyethylthio)acetate (4.90 g, Reference Compound No. 34-1)in methanol (100 ml) under ice cooling for 20 minutes. The temperatureis raised to room temperature, and the solution is stirred for 20 hours.The reaction solution is concentrated under reduced pressure, and theresulting residue is purified by silica gel column chromatography togive the titled reference compound (3.88 g).

[0404] IR(Film,cm⁻¹)3421, 3197, 1673, 1124, 1057

[0405] The following compound is obtained by a method similar toReference Example 38.

[0406] 2-(2,2-Dimethoxybutylthio)acetamide (Reference Compound No. 38-2)

[0407] IR(Film,cm⁻¹)3368, 3174, 1643, 1460, 1431, 1403, 1385, 1345, 1304

Reference Example 39

[0408] 3,4-Dihydro-2H-1,4-thiazin-3-one (Reference Compound No. 39-1)

[0409] p-Toluenesulfonic acid monohydrate (catalytic amount) is added toa solution of 2-(2,2-diethoxyethylthio)acetamide (3.19 g, ReferenceCompound No. 38-1) in toluene (30 ml), and the mixture is refluxed for15 hours. The reaction mixture is allowed to stand at room temperatureand washed with a saturated aqueous sodium hydrogencarbonate solutionand saturated brine successively. The organic layer is dried overanhydrous magnesium sulfate and concentrated under reduced pressure, andthe resulting residue is purified by silica gel column chromatography togive the titled reference Compound (1.21 g).

[0410] mp 73.0-74.0° C.

[0411] IR(KBr,cm⁻¹)3252, 3106, 3003, 1615, 1468, 1382, 1320, 1240

[0412] The following compound is obtained by a method similar toReference Example 39.

[0413] 5-Ethyl-3,4-dihydro-2H-1,4-thiazin-3-one (Reference Compound No.

[0414] 39-2)

[0415] IR(KBr,cm⁻¹)3191, 3081, 1691, 1635, 1484, 1456, 1439, 1405, 1371,1274, 1230

Reference Example 40

[0416] 2-Mercaptoacetamide (Reference Compound No. 40-1)

[0417] An ammonia gas is bubbled through methyl thioglycolate (3.00 g)for four hours. Nitrogen is bubbled through the reaction mixture toreplace ammonia with nitrogen. The resulting methanol is distilled awayunder reduced pressure to give the titled reference compound (2.15 g).

[0418] IR(KBr,cm⁻¹)3370, 2546, 1655, 1381, 1248

Reference Example 41.

[0419] 5-Phenyl-3,4-dihydro-2H-1,4-thiazin-3-one (Reference Compound No.41-1)

[0420] Triethylamine (4.55 g) is added to a solution of2-mercaptoacetamide (8.00 g, Reference compound No. 40-1) in ethanol (70ml), then phenacyl bromide (17.5 g) is added to the mixture, and thewhole is stirred for four hours. The reaction mixture is concentratedunder reduced pressure, water and 0.1 N hydrochloric acid are added tothe resulting residue, and the whole is extracted with ethyl acetate.The extract is washed with saturated brine and dried over anhydrousmagnesium sulfate. The extract is concentrated under reduced pressure.The resulting residue is suspended in ethanol (200 ml),p-toluenesulfonic acid monohydrate (catalytic amount) is added to thesuspension, and the mixture is refluxed for five days. The reactionmixture is cooled to room temperature to precipitate crystals. Thecrystals are filtered off and washed with ethanol to give the titledreference compound (11.6 g).

[0421] mp 158.0-160.0° C.

[0422] IR(KBr,cm⁻¹)3174, 3072, 1666, 1471

[0423] The following compounds are obtained by a method similar toReference Example 41.

[0424] 5-(4-Fluorophenyl)-3,4-dihydro-2H-1,4-thiazin-3-one (ReferenceCompound No. 41-2)

[0425] mp 142.0-160.0° C.

[0426] IR(KBr,cm⁻¹)3072, 1659, 1459, 1157

[0427] 5-(4-Methoxyphenyl)-3,4-dihydro-2H-1,4-thiazin-3-one (ReferenceCompound No. 41-3)

[0428] mp 150.0-152.5° C.

[0429] IR(KBr,cm⁻¹)3213, 1670, 1608, 1515

Reference Example 42

[0430] (2RS)-2-Isopropyl-3,4-dihydro-2H-1,4-thiazin-3-one (ReferenceCompound No. 42-1)

[0431] A solution of lithium diisopropylamide (10.4 mmol) intetrahydrofuran (5 ml) is cooled to −78° C. under a nitrogen atmosphere,and a solution of 3,4-dihydro-2H-1,4-thiazin-3-one (500 mg, ReferenceCompound No. 39-1) in tetrahydrofuran (5 ml) is added dropwise thereto.Then, 2-bromopropane (640 mg) is added dropwise thereto, and the mixtureis stirred for three hours. The temperature is raised to roomtemperature, and the mixture is stirred for two days. Water is added tothe reaction mixture under ice cooling, and the whole is extracted withethyl acetate. The extract is washed with water and saturated brinesuccessively and dried over anhydrous magnesium sulfate. The extract isconcentrated under reduced pressure, and the resulting residue ispurified by silica gel column chromatography to give the titledreference compound (100 mg).

[0432] mp 101.0-105.5° C.

[0433] IR(KBr,cm⁻¹)3188, 1664, 1613

[0434] The following compounds are obtained by a method similar toReference Example 42.

[0435] (2RS)-5-Ethyl-2-isopropyl-3,4-dihydro-2H-1,4-thiazin-3-one(Reference Compound No. 42-2)

[0436] (2RS)-2-Isopropyl-5-phenyl-3,4-dihydro-2H-1,4-thiazin-3-one(Reference Compound No. 42-3)

[0437] mp 134.5-140.5° C.

[0438] IR(KBr,cm⁻¹)3186, 3072, 1657, 1469, 1340

[0439](2RS)-5-(4-Fluorophenyl)-2-isopropyl-3,4-dihydro-2H-1,4-thiazin-3-one(Reference Compound No. 42-4)

[0440] IR(KBr,cm⁻¹)3190, 3069, 1660, 1608, 1509, 1237

[0441](2RS)-2-Isopropyl-5-(4-methoxyphenyl)-3,4-dihydro-2H-1,4-thiazin-3-one(Reference Compound No. 42-5)

[0442] mp 99.0-110.0° C.

[0443] IR(KBr,cm⁻¹)3187, 3066, 1660, 1607, 1513, 1256

[0444] (2RS)-2-Methyl-3,4-dihydro-2H-1,4-thiazin-3-one (ReferenceCompound No. 42-6)

[0445] IR(KBr,cm⁻¹)3238, 1664, 1445, 1381

[0446] (2RS)-2-Ethyl-3,4-dihydro-2H-1,4-thiazin-3-one (ReferenceCompound No. 42-7)

[0447] IR(KBr,cm⁻¹)3775, 3231, 3082, 2967, 2875, 1673, 1456, 1378

[0448] (2RS)-2-Propyl-3,4-dihydro-2H-1,4-thiazin-3-one (ReferenceCompound No. 42-8)

[0449] IR(KBr,cm⁻¹)3189, 3073, 1670, 1614, 1387

[0450] (2RS)-2-(2-Methoxyethyl)-3,4-dihydro-2H-1,4-thiazin-3-one(Reference Compound No. 42-9)

[0451] IR(Film,cm⁻¹)3238, 1674, 1618, 1117 Reference

Example 43

[0452] Methyl2-{(2RS)-2-isopropyl-3-oxo-3,4-dihydro-2H-1,4-thiazin-4-yl}acetate(Reference Compound No. 43-1)

[0453] A solution of (2RS)-2-isopropyl-3,4-dihydro-2H-1,4-thiazin-3-one(70 mg, Reference compound No. 42-1) in anhydrous tetrahydrofuran (1 ml)is added to a solution of sodium hydride (39 mg) in anhydroustetrahydrofuran (i ml) under ice cooling, and the mixture is stirred for10 minutes. Methyl bromoacetate (74.3 mg) is added to the mixture, thetemperature is raised to room temperature, and the whole is stirred for20 minutes. The reaction mixture is cooled with ice, water is added tothe mixture, and the whole is extracted with ethyl acetate. The extractis washed with 1 N hydrochloric acid, water and saturated brinesuccessively and dried over anhydrous magnesium sulfate. The extract isconcentrated under reduced pressure, and the resulting residue ispurified by silica gel column chromatography to give the titledreference compound (90.2 mg).

[0454] IR(Film,cm⁻¹) 1756, 1667, 1386, 1286

[0455] The following compounds are obtained by a method similar toReference Example 43.

[0456] Ethyl2-{(2RS)-5-ethyl-2-isopropyl-3-oxo-3,4-dihydro-2H-1,4-thiazin-4-yl}acetate(Reference Compound No. 43-2)

[0457] IR(Film,cm⁻¹) 1752, 1669, 1465, 1368, 1200

[0458] Methyl2-{(2RS)-2-isopropyl-3-oxo-5-phenyl-3,4-dihydro-2H-1,4-thiazin-4-yl}acetate(Reference Compound No. 43-3)

[0459] IR(Film,cm⁻¹)1754, 1674, 1209

[0460] Methyl2-{(2RS)-5-(4-fluorophenyl)-2-isopropyl-3-oxo-3,4-dihydro-2H-1,4-thiazin-4-yl}acetate(Reference Compound No. 43-4)

[0461] IR(Film,cm⁻¹)1754, 1673, 1508, 1365, 1213

[0462] Methyl2-{(2RS)-2-isopropyl-5-(4-methoxyphenyl)-3-oxo-3,4-dihydro-2H-1,4-thiazin-4-yl}acetate(Reference Compound No. 43-5)

[0463] mp. 99.0-110.0° C.

[0464] IR(Film,cm⁻¹) 1753, 1671, 1609, 1511, 1364, 1248, 1210, 1177

[0465] Methyl2-{(2RS)-2-methyl-3-oxo-3,4-dihydro-2H-1,4-thiazin-4-yl}acetate(Reference Compound No. 43-6)

[0466] IR(Film,cm⁻¹) 1753, 1667, 1389, 1207

[0467] Ethyl2-{(2RS)-2-ethyl-3-oxo-3,4-dihydro-2H-1,4-thiazin-4-yl}acetate(Reference Compound No. 43-7)

[0468] IR(Film,cm⁻¹)1749, 1667, 1455, 1385

[0469] Methyl2-{(2RS)-3-oxo-2-propyl-3,4-dihydro-2H-1,4-thiazin-4-yl}acetate(Reference Compound No. 43-8)

[0470] IR(Film,cm⁻¹) 1754, 1668, 1619, 1208

[0471] Methyl2-{(2RS)-2-(2-methoxyethyl)-3-oxo-3,4-dihydro-2H-1,4-thiazin-4-yl}acetate(Reference Compound No. 43-9)

[0472] IR(Film,cm⁻¹)1753, 1668, 1387, 1208

[0473] Methyl(2RS)-2-{(2RS)-2-isopropyl-3-oxo-3,4-dihydro-2H-1,4-thiazin-4-yl}propanoate(Reference Compound No. 43-10)

[0474] Ethyl(2RS)-2-{(2RS)-2-isopropyl-3-oxo-3,4-dihydro-2H-1,4-thiazin-4-yl}butyrate(Reference Compound No. 43-11)

[0475] Benzyl(2RS)-2-{(2RS)-2-isopropyl-3-oxo-3,4-dihydro-2H-1,4-thiazin-4-yl}-3-phenylpropanoate(Reference Compound No. 43-12)

Reference Example 44

[0476] 2-{(2RS)-2-Isopropyl-3-oxo-3,4-dihydro-2H-1,4-thiazin-4-yl}aceticacid (Reference Compound No. 44-1)

[0477] Methanol (0.15 ml) and a 1 N aqueous sodium hydroxide solution(0.34 ml) are added to a solution of methyl2-{(2RS)-2-isopropyl-3-oxo-3,4-dihydro-2H-1,4-thiazin-4-yl}acetate (70mg, Reference Compound No. 43-1) in tetrahydrofuran (0.15 ml) under icecooling, then the temperature is raised to room temperature, and themixture is stirred for 15 minutes. Diethyl ether is added to thereaction mixture, and the whole is extracted with water. 2 NHydrochloric acid is added to the extract to acidify the system, and thewhole is extracted with ethyl acetate. The extract is washed withsaturated brine and dried over anhydrous magnesium sulfate. The extractis concentrated under reduced pressure to give the titled referenceCompound (65.7 mg).

[0478] IR(KBr,cm⁻¹) 1733, 1627, 1390, 1201

[0479] The following compounds are obtained by a method similar toReference Example 44.

[0480]2-{(2RS)-5-Ethyl-2-isopropyl-3-oxo-3,4-dihydro-2H-1,4-thiazin-4-yl}aceticAcid (Reference Compound No. 44-2)

[0481]2-{(2RS)-2-Isopropyl-3-oxo-5-phenyl-3,4-dihydro-2H-1,4-thiazin-4-yl}aceticAcid (Reference Compound No. 44-3)

[0482] mp 107.5-111.0° C.

[0483] IR(Film,cm⁻¹)1749, 1627, 1185, 757

[0484]2-{(2RS)-5-(4-Fluorophenyl)-2-isopropyl-3-oxo-3,4-dihydro-2H-1,4-thiazin-4-yl}aceticAcid (Reference Compound No. 44-4)

[0485] mp 139.5-146.0° C.

[0486] IR(KBr,cm⁻¹)3279, 1752, 1724, 1673, 1605, 1507

[0487]2-{(2RS)-2-Isopropyl-5-(4-methoxyphenyl)-3-oxo-3,4-dihydro-2H-1,4-thiazin-4-yl}aceticAcid (Reference Compound No. 44-5)

[0488] IR(Film,cm⁻¹)3440, 1732, 1609, 1510

[0489] 2-{(2RS)-2-Methyl-3-oxo-3,4-dihydro-2H-1,4-thiazin-3-one}aceticacid (Reference Compound No. 44-6)

[0490] mp 72.0-80.5° C.

[0491] IR(Film,cm⁻¹)1735, 1629, 1434, 1402, 1199

[0492] 2-{(2RS)-2-Ethyl-3-oxo-3,4-dihydro-2H-1,4-thiazin-4-yl}aceticAcid (Reference Compound No. 44-7)

[0493] IR(Film,cm⁻¹)1731, 1662, 1393, 1355

[0494] 2-{(2RS)-3-Oxo-2-propyl-3,4-dihydro-2H-1,4-thiazin-4-yl}aceticAcid (Reference Compound No. 44-8)

[0495]2-{(2RS)-2-(2-Methoxyethyl)-3-oxo-3,4-dihydro-2H-1,4-thiazin-4-yl}aceticAcid (Reference Compound No. 44-9)

[0496] IR(Film,cm⁻¹)3422, 1729, 1642, 1397, 1217

[0497](2RS)-2-{(2RS)-2-Isopropyl-3-oxo-3,4-dihydro-2H-1,4-thiazin-4-yl}propanoicAcid (Reference Compound No. 44-10)

[0498](2RS)-2-{(2RS)-3,4-Dihydro-2-isopropyl-3-oxo-2H-1,4-thiazin-4-yl}butyricAcid (Reference Compound No. 44-11)

[0499](2RS)-2-{(2RS)-2-Isopropyl-3-oxo-3,4-dihydro-2H-1,4-thiazin-4-yl}-3-phenylpropanoicAcid (Reference Compound No. 44-12)

Reference Example 45

[0500] DL-Valine Methyl Ester Hydrochloride (Reference Compound No.45-1)

[0501] Methanol (50 ml) is cooled to −15° C., then thionyl chloride(21.2 g) is added dropwise to the methanol, and the solution is stirredfor 20 minutes. DL-Valine is added to the solution, and the mixture isstirred overnight. The reaction mixture is concentrated under reducedpressure, and diethyl ether is added to the resulting residue toprecipitate crystals. The precipitated crystals are filtered off to givethe titled reference compound (8.68 g).

[0502] D-Valine Methyl Ester Hydrochloride (Reference Compound No. 45-2)

[0503] mp 162.5-166.0° C.

[0504] [α]_(D) ²¹-24.0° (c=2.0, methanol)

[0505] IR(KBr,cm⁻¹)3463, 2975, 1981, 1740, 1595, 1508

[0506] The following compounds are obtained by a method similar toReference Example 45.

[0507] L-Valine Methyl Ester Hydrochloride (Reference Compound No. 45-3)

[0508] Glycine Methyl Ester Hydrochloride (Reference Compound No. 45-4)

[0509] Methyl 2-aminoisobutyrate Hydrochloride (Reference Compound No.45-5)

[0510] mp 186.0-186.5° C.

[0511] IR(KBr,cm⁻¹)2960, 1748, 1596, 1522, 1468, 1438

[0512] Methyl (2RS)-2-aminobutyrate Hydrochloride (Reference CompoundNo. 45-6)

[0513] mp 148.0-149.1° C.

[0514] IR(KBr,cm⁻¹)2958, 1748, 1591, 1522, 1455

[0515] DL-Isoleucine Methyl Ester Hydrochloride Reference Compound No.45-7)

[0516] IR(KBr,cm⁻¹)3416, 1745, 1595, 1510, 1442

[0517] DL-Leucine Methyl Ester Hydrochloride (Reference Compound No.45-8)

[0518] mp 136.5-138.9° C.

[0519] IR(KBr,cm⁻¹)2960, 1756, 1517, 1232

[0520] DL-Cyclohexylglycine Methyl Ester Hydrochloride (ReferenceCompound No. 45-9)

[0521] mp 150.0-157.0° C.

[0522] IR(KBr,cm⁻¹) 1740, 1590, 1522, 1442

[0523] DL-Threonine Methyl Ester Hydrochloride (Reference Compound No.45-10)

[0524] IR(KBr,cm⁻¹)3441, 2633, 1752, 1594, 1509

[0525] Methyl (2RS)-2-amino-3 methoxypropionate Hydrochloride (ReferenceCompound No. 45-11)

[0526] mp 138.2-139.4° C.

[0527] IR(KBr,cm⁻¹)2935, 1747, 1587, 1519, 1477, 1441

[0528] DL-Phenylglycine methyl ester hydrochloride (Reference CompoundNo. 45-12)

[0529] IR(KBr,cm⁻¹) 1744, 1581, 1514, 1494, 1460, 1430

Reference Example 46

[0530] Methyl (2RS)-2-(2-oxo-2-phenylethyl)aminoisovalerate (ReferenceCompound No. 46-1)

[0531] Diisopropylethylamine (7.66 ml) and 2-bromoacetophenone (4.2 g)are added to a suspension of DL-valine methyl ester hydrochloride (3.36g, Reference Compound No. 45-1) in methylene chloride (100 ml), and themixture is refluxed for four days. The reaction mixture is allowed tostand at room temperature, diethyl ether is added to the mixture, andthe whole is extracted with 0.1 N hydrochloric acid. Sodiumhydrogencarbonate is added to the extract to basify the system, and thewhole is extracted with ethyl acetate. The organic layer is washed withsaturated brine and dried over magnesium sulfate. The organic layer isconcentrated under reduced pressure to give the titled referenceCompound (4.92 g).

[0532] mp 32.5-50.8° C.

[0533] IR(KBr,cm⁻¹)3334, 2964, 2614, 1730, 1687, 1598, 1448

[0534] The following compounds are obtained by a method similar toReference Example 46.

[0535] Methyl (2R)-2-(2-oxo-2-phenylethyl)aminoisovalerate (Referencecompound No. 46-2)

[0536] mp 41.5-46.0° C.

[0537] [α]_(D) ²⁰ +33.6° (c=1.0, methanol)

[0538] IR(KBr,cm⁻¹)3333, 3085, 3029, 3000, 2971, 2954, 1727, 1685, 1596

[0539] Methyl (2S)-2-(2-oxo-2-phenylethyl)aminoisovalerate (ReferenceCompound No. 46-3)

[0540] mp 44.0-48.5° C.

[0541] IR(KBr,cm⁻¹)3436, 3333, 2954, 1727, 1685, 1596, 1580, 1468, 1449

[0542] Ethyl 2-(2-oxo-2-phenylethyl)aminoacetate (Reference Compound No.46-4)

[0543] Methyl 2-(2-oxo-2-phenylethyl)aminoisobutyrate (ReferenceCompound No. 46-5)

[0544] mp 51.0-61.0° C.

[0545] IR(KBr,cm⁻¹)3327, 1725, 1683, 1593, 1450

[0546] Methyl (2RS)-2-(2-oxo-2-phenylethyl)aminobutyrate (ReferenceCompound No. 46-6)

[0547] IR(KBr,cm⁻¹)3333, 1736, 1690, 1598, 1550, 1447

[0548] Methyl (2RS, 3RS)-3-methyl-2-(2-oxo-2-phenylethyl)aminopentanoate(Reference Compound No. 46-7)

[0549] IR(Film,cm⁻¹)3330, 1736, 1691, 1597, 1580, 1546, 1529, 1502

[0550] Methyl (2RS)-4-methyl-2-(2-oxo-2-phenylethyl)aminopentanoate(Reference Compound No. 46-8)

[0551] IR(KBr,cm⁻¹)3323, 1730, 1684, 1453

[0552] Methyl (2RS)-2-cyclohexyl-2-(2-oxo-2-phenylethyl)aminoacetate(Reference Compound No. 46-9)

[0553] IR(Film,cm⁻¹)3323, 1727, 1687, 1597, 1581, 1495, 1450

[0554] Methyl (2RS, 3RS)-3-hydroxy-2-(2-oxo-2-phenylethyl)aminobutyrate(Reference Compound No. 46-10)

[0555] mp 76.0-78.5° C.

[0556] IR(KBr,cm⁻¹)3067, 1737, 1604, 1449

[0557] Methyl (2RS)-3-methoxy-2-(2-oxo-2-phenylethyl)aminopropionate(Reference Compound No. 46-11)

[0558] IR(KBr,cm⁻¹)3345, 3061, 1740, 1691, 1598, 1581, 1449

[0559] Ethyl (2RS)-4-methoxy-2-(2-oxo-2-phenylethyl)aminobutyrate(Reference Compound No. 46-12)

[0560] IR(Film,cm⁻¹)3322, 1735, 1688, 1598, 1580, 1528, 1448

[0561] Methyl (2RS)-2-(2-oxo-2-phenylethyl)amino-2-phenylacetate(Reference Compound No. 46-13)

[0562] mp 45.0-54.0° C.

[0563] IR(KBr,cm⁻¹)3332, 3083, 3023, 1741, 1686, 1597, 1580, 1447

[0564] Methyl(2RS)-2-{2-oxo-2-(3,4,5-trimethoxyphenyl)ethyl}aminoisovalerate(Reference Compound No. 46-14)

[0565] mp 103.0-104.3° C.

[0566] IR(KBr,cm⁻¹)3332, 2961, 2842, 1726, 1677, 1585, 1511, 1467

[0567] Methyl(2RS)-2-{2-(3,4-dimethoxyphenyl)-2-oxoethyl}aminoisovalerate (ReferenceCompound No. 46-15)

[0568] IR(Film,cm⁻¹)3338, 2960, 2840, 1732, 1679, 1595, 1516, 1514

[0569] Methyl (2RS)-2-{2-(3-methoxyphenyl)-2-oxoethyl}aminoisovalerate(Reference Compound No. 46-16)

[0570] Methyl (2R)-2-{2-(3-methoxyphenyl)-2-oxoethyl}aminoisovalerate(Reference Compound No. 46-17)

Reference Example 47

[0571] Methyl (2RS)-2-{N-acetyl-N-(2-oxo-2-phenylethyl)}aminoisovalerate(Reference Compound No. 47-1)

[0572] Pyridine (10.7 ml) is added to a solution of methyl(2RS)-2-(2-oxo-2-phenylethyl)aminoisovalerate (16.5 g, Referencecompound No. 46-1) in methylene chloride (70 ml). The mixture is cooledwith ice, and acetyl chloride (7.06 ml) is added to the mixture. Then,the temperature is raised to room temperature, and the whole is stirredovernight. The reaction mixture is concentrated under reduced pressure,and the resulting residue is diluted with ethyl acetate. The dilutedsolution is washed with hydrochloric acid, a saturated aqueous sodiumhydrogencarbonate solution and saturated brine successively and driedover anhydrous magnesium sulfate. The diluted solution is concentratedunder reduced pressure, and the resulting residue is purified by silicagel column chromatography to give the titled reference compound (18.6g).

[0573] mp 85.5-86.0° C.

[0574] IR(KBr,cm⁻¹) 1729, 1697, 1640

[0575] The following compounds are obtained by a method similar toReference Example 47.

[0576] Methyl (2R)-2-{N-acetyl-N-(2-oxo-2-phenylethyl)}aminoisovalerate(Reference Compound No. 47-2)

[0577] [α]_(D) ²⁰ +70.7° (c=1.1, methanol)

[0578] IR(Film,cm⁻¹)3454, 2965, 2875, 1738, 1702, 1653, 1598, 1449

[0579] Methyl (2S)-2-{N-acetyl-N-(2-oxo-2-phenylethyl)}aminoisovalerate(Reference Compound No. 47-3)

[0580] [α]_(D) ²⁰ −74.5° (c=0.99, methanol)

[0581] IR(Film,cm⁻¹)3460, 2964, 2875, 1739, 1701, 1653, 1598, 1581, 1449

[0582] Ethyl 2-{N-acetyl-N-(2-oxo-2-phenylethyl)}aminoacetate (ReferenceCompound No. 47-4)

[0583] Methyl 2-{N-acetyl-N-(2-oxo-2-phenylethyl)}aminoisobutyrate(Reference Compound No. 47-5)

[0584] IR(Film,cm⁻¹) 1736, 1698, 1649, 1596, 1580

[0585] Methyl (2RS)-2-{N-acetyl-N-(2-oxo-2-phenylethyl)}aminobutyrate(Reference Compound No. 47-6)

[0586] IR(Film,cm⁻¹) 1737, 1702, 1654, 1597, 1580, 1449

[0587] Methyl (2RS,3RS)-2-{N-acetyl-N-(2-oxo-2-phenylethyl)}amino-3-methylpentanoate(Reference Compound No. 47-7)

[0588] IR(Film,cm⁻¹)1739, 1702, 1657, 1598, 1581

[0589] Methyl(2RS)-2-{N-acetyl-N-(2-oxo-2-phenylethyl)}amino-4-methylpentanoate(Reference Compound No. 47-8)

[0590] mp 66.6-68.3° C.

[0591] IR(Film,cm⁻¹)1729, 1702, 1635, 1582, 1471, 1452

[0592] Methyl(2RS)-2-{N-acetyl-N-(2-oxo-2-phenylethyl)}amino-2-cyclohexylacetate(Reference Compound No. 47-9)

[0593] IR(Film,cm⁻¹)3006, 1734, 1702, 1654, 1598, 1581

[0594] Methyl (2RS,3RS)-2-{N-acetyl-N-(2-oxo-2-phenylethyl)}amino-3-tert-butyldimethylsilyloxybutyrate(Reference Compound No. 47-10)

[0595] IR(Film,cm⁻¹)3062, 1745, 1705, 1660, 1598, 1581

[0596] Methyl (2RS)-2-{N-acetyl-N-(2-oxo-2-phenylethyl)}amino-3-methoxypropionate (Reference Compound No. 47-11)

[0597] IR(Film,cm⁻¹) 1745, 1699, 1655, 1598, 1449

[0598] Methyl(2RS)-2-{N-acetyl-N-(2-oxo-2-phenylethyl)}amino-4-methoxybutyrate(Reference Compound No. 47-12)

[0599] IR(Film,cm⁻¹)1736, 1702, 1658, 1597, 1580

[0600] Methyl(2RS)-2-{N-acetyl-N-(2-oxo-2-phenylethyl)}amino-2-phenylacetate(Reference Compound No. 47-13)

[0601] mp 133.5-136.0° C.

[0602] IR(KBr,cm⁻¹)3037, 3008, 1742, 1685, 1645, 1598, 1580

[0603] Methyl(2RS)-2-{N-isobutyryl-N-(2-oxo-2-phenylethyl)}aminoisovalerate(Reference Compound No. 47-14)

[0604] IR(Film,cm⁻¹)1737, 1702, 1654, 1470

[0605] Methyl(2R)-2-{N-isobutyryl-N-(2-oxo-2-phenylethyl)}aminoisovalerate (ReferenceCompound No. 47-15)

[0606] [α]_(D) ²⁰ +59.1° (c=1.0, methanol)

[0607] IR(KBr,cm⁻¹)1732, 1697, 1648, 1450

[0608] Methyl(2RS)-2-{N-(2-oxo-2-phenylethyl)-N-pivaloyl}aminoisovalerate (ReferenceCompound No. 47-16)

[0609] Methyl(2RS)-2-{N-cydohexylcarbonyl-N-(2-oxo-2-phenylethyl)}-aminoisovalerate(Reference Compound No. 47-17)

[0610] IR(Film,cm⁻¹)2931, 2854, 1737, 1701, 1648, 1598, 1449

[0611] Methyl(2R)-2-{N-methoxyacetyl-N-(2-oxo-2-phenylethyl)}aminoisovalerate(Reference Compound No. 47-18)

[0612] [α]_(D) ²⁰ +53.1° (c=1.0, methanol)

[0613] IR(Film,cm⁻¹)2963, 2876, 2825, 1738, 1700, 1666, 1448

[0614] Methyl (2R)-2-{N-benzoyl-N-(2-oxo-2-phenylethyl)}aminoisovalerate(Reference Compound No. 47-19)

[0615] [α]_(D) ²⁰ +88.6° (c-1.0, methanol)

[0616] IR(Film,cm⁻¹)2963, 1739, 1702, 1645, 1599, 1580, 1493, 1448

[0617] Methyl(2RS)-2-{N-(4-chlorobenzoyl)-N-(2-oxo-2-phenylethyl)}aminoisovalerate(Reference Compound No. 47-20)

[0618] IR(KBr,cm⁻¹)1740, 1701, 1646, 1597

[0619] Methyl(2RS)-2-{N-(4-methoxybenzoyl)-N-(2-oxo-2-phenylethyl)}-aminoisovalerate(Reference Compound No. 47-21)

[0620] IR(Film,cm⁻¹) 1740, 1707

[0621] Methyl(2RS)-2-{N-(4-nitrobenzoyl)-N-(2-oxo-2-phenylethyl)}aminoisovalerate(Reference Compound No. 47-22)

[0622] mp 117° C.

[0623] IR(KBr,cm⁻¹)1743, 1711, 1657, 1600, 1531

[0624] Methyl(2RS)-2-{N-(2-oxo-2-phenylethyl)-N-(3-phenylpropanoyl)}-aminoisovalerate(Reference Compound No. 47-23)

[0625] IR(Film,cm⁻¹)3379, 3061, 3027, 2963, 2874, 1738, 1701, 1656, 1449

[0626] Methyl(2RS)-2-{N-(2-oxo-2-phenylethyl)-N-phenoxyacetyl}aminoisovalerate(Reference Compound No. 47-24)

[0627] mp 100.0-109.5° C.

[0628] IR(KBr,cm⁻¹)3375, 3056, 2958, 2875, 1729, 1696, 1660, 1591, 1496

[0629] Methyl(2RS)-2-{N-(2-oxo-2-phenylethyl)-N-(2-pyridylcarbonyl)}-aminoisovalerate(Reference Compound No. 47-25)

[0630] IR(Film,cm⁻¹) 1737, 1701, 1646, 1449

[0631] Methyl(2RS)-2-{N-(2-oxo-2-phenylethyl)-N-(3-pyridylcarbonyl)}-aminoisovalerate(Reference Compound No. 47-26)

[0632] IR(Film,cm⁻¹)2964, 2875, 1740, 1701, 1645, 1590

[0633] Methyl(2RS)-2-{N-(2-oxo-2-phenylethyl)-N-(4-pyridylcarbonyl)}aminoisovarelate(Reference Compound No. 47-27)

[0634] IR(Film,cm⁻¹)2965, 2875, 1741, 1703, 1650, 1597, 1582

[0635] Methyl(2RS)-2-{N-(2-oxo-2-phenylethyl)-N-phenylsulfonyl}aminoisovalerate(Reference Compound No. 47-28)

[0636] IR(Film,cm⁻¹) 1740, 1707

[0637] Methyl(2RS)-2-[N-acetyl-N-{2-oxo-2-(3,4,5-trimethoxyphenyl)ethyl}]aminoisovalerate(Reference Compound No. 47-29)

[0638] IR(Film,cm⁻¹)2964, 2840, 1739, 1696, 1652, 1586, 1540, 1506, 1456

[0639] Methyl(2RS)-2-[N-benzoyl-N-{2-oxo-2-(3,4,5-trimethoxyphenyl)ethyl}]aminoisovalerate(Reference Compound No. 47-30)

[0640] IR(KBr,cm⁻¹)2964, 2840, 2645, 1742, 1696, 1642, 1586, 1540, 1506

[0641] Methyl(2RS)-2-[N-methoxyacetyl-N-{2-oxo-2-(3,4,5-trimethoxyphenyl)ethyl}]aminoisovalerate(Reference Compound No. 47-31)

[0642] IR(Film,cm⁻¹)2962, 2829, 1740, 1692, 1664, 1586, 1506, 1453

[0643] Methyl(2RS)-2-[N-acetyl-N-{2-(3,4-dimethoxyphenyl)-2-oxoethyl}]-aminoisovalerate(Reference Compound No. 47-32)

[0644] IR(Film,cm⁻¹)2964, 2875, 2841, 1738, 1691, 1650, 1596, 1547, 1517

[0645] Methyl(2RS)-2-[N-benzoyl-N-{2-(3,4-dimethoxyphenyl)-2-oxoethyl}]-aminoisovalerate(Reference Compound No. 47-33)

[0646] IR(Film,cm⁻¹)3011, 2964, 2874, 2840, 1739, 1689, 1644, 1596, 1515

[0647] Methyl (2RS)-2-[N-{2-(3,4-dimethoxyphenyl)-2oxoethyl}-N-methoxyacetyl]aminoisovalerate (Reference Compound No.47-34)

[0648] IR(Film,cm⁻¹)2962, 2839, 1738, 1688, 1596, 1553, 1516, 1454

[0649] Methyl(2RS)-2-[N-benzoyl-N-{2-(3-methoxyphenyl)-2-oxoethyl}]aminoisovalerate(Reference Compound No. 47-35)

[0650] Methyl(2RS)-2-{N-methoxyacetyl-N-(2-oxo-2-phenylethyl)}aminoisovalerate(Reference Compound No. 47-36)

[0651] Methyl(2RS)-2-{N-benzoyl-N-(2-oxo-2-phenylethyl)}aminoisovalerate (ReferenceCompound No. 47-37)

[0652] Methyl(2R)-2-{N-(2-oxo-2-phenylethyl)-N-(2-pyridylcarbonyl)}aminoisovalerate(Reference Compound No. 47-38)

[0653] Methyl(2R)-2-{N-(2-oxo-2-phenylethyl)-N-(3-pyridylcarbonyl)}aminoisovalerate(Reference Compound No. 47-39)

[0654] Methyl(2R)-2-{N-(2-oxo-2-phenylethyl)-N-(4-pyridylcarbonyl)}aminoisovalerate(Reference Compound No. 47-40)

[0655] Methyl(2R)-2-[N-acetyl-N-{2-(3-methoxyphenyl)-2-oxoethyl}]aminoisovalerate(Reference Compound No. 47-41)

Reference Example 48

[0656] (2RS)-2-{N-Acetyl-N-(2-oxo-2-phenylethyl)}aminoisovaleramide(Reference Compound No. 48-1)

[0657] A solution of methyl(2RS)-2-{N-acetyl-N-(2-oxo-2-phenylethyl)}-amnoisovalerate (1.0 g,Reference compound No. 47-1) in methanol (5 ml) is saturated with anammonia gas, and then the solution is sealed and stirred for six days.The reaction solution is concentrated under reduced pressure, and theresulting residue is purified by silica gel column chromatography togive the titled reference compound (926 mg).

[0658] IR(Film,cm⁻¹)3121, 1659, 1448, 1297

[0659] The following compounds are obtained by a method similar toReference Example 48.

[0660] (2R)-2-{N-Acetyl-N-(2-oxo-2-phenylethyl)}aminoisovaleramide(Reference Compound No. 48-2)

[0661] [α]_(D) ²⁰ +3.1° (c=1.1, methanol)

[0662] IR(KBr,cm⁻¹)3215, 2965, 2874, 1668, 1449

[0663] (2S)-2-{N-Acetyl-N-(2-oxo-2-phenylethyl)}aminoisovaleramide(Reference Compound No. 48-3)

[0664] [α]_(D) ²⁰ −3.0° (c=1.0, methanol)

[0665] IR(KBr,cm⁻¹)3233, 2964, 2874, 1670, 1449

[0666] 2-{N-Acetyl-N-(2-oxo-2-phenylethyl)}aminoacetamide (ReferenceCompound No. 48-4)

[0667] 2-{N-Acetyl-N-(2-oxo-2-phenylethyl)}aminoisobutyramide (ReferenceCompound No. 48-5)

[0668] IR(Film,cm⁻¹)3208, 1682, 1597, 1449

[0669] (2RS)-2-{N-Acetyl-N-(2-oxo-2-phenylethy)}aminobutyramide(Reference Compound No. 48-6)

[0670] IR(Film,cm⁻¹)3242, 1663, 1449

[0671] (2RS,3RS)-2-{N-Acetyl-N-(2-oxo-2-phenylethyl)}amino-3-methylpentanamide(Reference Compound No. 48-7)

[0672] IR(Film,cm⁻¹)3208, 1659, 1449

[0673](2RS)-2-{N-Acetyl-N-(2-oxo-2-phenylethyl)}amino-4-methylpentanamide(Reference Compound No. 48-8)

[0674] mp 166.7-170.7° C.

[0675] IR(KBr,cm⁻¹)3320, 3284, 1661, 1630, 1467, 1423

[0676](2RS)-2-{N-Acetyl-N-(2-oxo-2-phenylethyl)}amino-2-cyclohexylacetamide(Reference Compound No. 48-9).

[0677] mp 175.0-192.3° C.

[0678] IR(KBr,cm⁻¹)3271, 3060, 3020, 1656, 1640, 1467

[0679] (2RS,3RS)-2-{N-Acetyl-N-(2-oxo-2-phenylethyl)}amino-3-tert-butyldimethylsilyloxybutyramide(Reference Compound No. 48-10)

[0680] IR(Film,cm⁻¹)3197, 3089, 1674, 1435

[0681](2RS)-2-{N-Acetyl-N-(2-oxo-2-phenylethyl)}amino-3-methoxypropionamide(Reference Compound No. 48-11)

[0682](2RS)-2-{N-Acetyl-N-(2-oxo-2-phenylethyl)}amino-4-methoxybutyramide(Reference Compound No. 48-12)

[0683] IR(Film,cm⁻¹)3246, 1666, 1448

[0684] (2RS)-2-{N-Acetyl-N-(2-oxo-2-phenylethyl)}amino-2-phenylacetamide(Reference Compound No. 48-13)

[0685] mp 174.5-176.5° C.

[0686] IR(KBr,cm⁻¹)3276, 3016, 1660, 1642, 1602, 1497

[0687] (2RS)-2-{N-Formyl-N-(2-oxo-2-phenylethyl)}aminoisovaleramide(Reference Compound No. 48-14)

[0688] IR(Film,cm⁻¹)3212, 2964, 1666, 1449

[0689] (2RS)-2-{N-Isobutyryl-N-(2-oxo-2-phenylethyl)}aminoisovaleramide(Reference Compound No. 48-15)

[0690] (2R)-2-{N-Isobutyryl-N-(2-oxo-2-phenylethyl)}aminoisovaleramide(Reference Compound No. 48-16)

[0691] (2RS)-2-{N-(2-Oxo-2-phenylethyl)-N-pivaloyl}aminoisovaleramide(Reference Compound No. 48-17)

[0692] IR(Film,cm⁻¹)3338, 2965, 2875, 1668, 1650, 1643, 1633, 1469

[0693] (2RS)-2-{N-Cydohexylcarbonyl-N-(2-oxo-2-phenylethyl)}aminoisovaleramide (Reference Compound No. 48-18)

[0694] IR(Film,cm⁻¹)3260, 2931, 2854, 1664, 1449

[0695](2RS)-2-{N-Methoxycarbonyl-N-(2-oxo-2-phenylethyl)}aminoisovaleramide(Reference Compound No. 48-19)

[0696] mp 133.5-136.0° C.

[0697] IR(KBr,cm⁻¹)3233, 2961, 1690, 1653, 1471

[0698](2RS)-2-{N-Ethoxycarbonyl-N-(2-oxo-2-phenylethyl)}aminoisovaleramide(Reference Compound No. 48-20)

[0699] IR(Film,cm⁻¹)3345, 2965, 1681, 1448

[0700] (2R)-2-{N-Methoxyacetyl-N-(2-oxo-2-phenylethy)}aminoisovaleramide (Reference Compound No. 48-21)

[0701] [α]_(D) ²⁰ −0.8° (c=0.52, methanol)

[0702] IR(Film,cm⁻¹)3270, 2963, 2825, 1666, 1449

[0703] (2R)-2-{N-Benzoyl-N-(2-oxo-2-phenylethyl)}aminoisovaleramide(Reference Compound No. 48-22)

[0704] [α]_(D) ²⁰ +12.1° (c=1.0, methanol)

[0705] IR(Film,cm⁻¹)3349, 2964, 1667, 1494, 1448

[0706](2RS)-2-{N-(4-Chlorobenzoyl)-N-(2-oxo-2-phenylethyl)}aminoisovarelamide(Reference Compound No. 48-23)

[0707](2RS)-2-{N-(4-Methoxybenzoyl)-N-(2-oxo-2-phenylethyl)}aminoisovaleramide(Reference Compound No. 48-24)

[0708](2RS)-2-{N-(4-Nitrobenzoyl)-N-(2-oxo-2-phenylethyl)}aminoisovaleramide(Reference Compound No. 48-25)

[0709](2RS)-2-{N-(2-Oxo-2-phenylethyl)-N-(3-phenylpropanoyl)}aminoisovaleramide(Reference Compound No. 48-26)

[0710] IR(Film,cm⁻¹)3338, 3062, 3027, 2963, 2874, 1662, 1496, 1450

[0711](2RS)-2-{N-Benzyloxycarbonyl-N-(2-oxo-2-phenylethyl)}aminoisovaleramide(Reference Compound No. 48-27)

[0712] IR(Film,cm⁻¹)3341, 2964, 1679, 1450

[0713](2RS)-2-{N-(2-Oxo-2-phenylethyl)-N-phenoxyacetyl}aminoisovaleramide(Reference Compound No. 48-28)

[0714] IR(Film,cm⁻¹)3339, 3064, 3012, 2965, 2874, 1666, 1599, 1496, 1449

[0715](2RS)-2-{N-(2-Oxo-2-phenylethyl)-N-(2-thienylcarbonyl)}aminoisovaleramide(Reference Compound No. 48-29)

[0716] mp 137.0-138.5° C.

[0717] IR(KBr,cm⁻¹)3266, 2964, 1662, 1616, 1522, 1448

[0718](2RS)-2-{N-(2-Oxo-2-phenylethyl)-N-(2-pyridylcarbonyl)}aminoisovaleramide(Reference Compound No. 48-30)

[0719](2RS)-2-{N-(2-Oxo-2-phenylethy)-N-(3-pyridylcarbonyl)}aminoisovaleramide(Reference Compound No. 48-31)

[0720] IR(Film,cm⁻¹)3209, 2964, 1646

[0721](2RS)-2-{N-(2-Oxo-2-phenylethyl)-N-(4-pyridylcarbonyl)}aminoisovaleramide(Reference Compound No. 48-32)

[0722] IR(Film,cm⁻¹)3204, 1650, 1552, 1494, 1448

[0723](2RS)-2-{N-Methanesulfonyl-N-(2-oxo-2-phenylethyl)}aminoisovaleramide(Reference Compound No. 48-33)

[0724] IR(Film,cm⁻¹)3212, 1659, 1448, 1292

[0725](2RS)-2-{N-Benzenesulfonyl-N-(2-oxo-2-phenylethyl)}aminoisovaleramide(Reference Compound No. 48-34)

[0726](2RS)-2-[N-Acetyl-N-{2-oxo-2-(3,4,5-trimethoxyphenyl)ethyl}]aminoisovaleramide(Reference Compound No. 48-35)

[0727] IR(Film,cm⁻¹)3305, 2965, 2837, 1667, 1591, 1506, 1463

[0728](2RS)-2-[N-Benzoyl-N-{2-oxo-2-(3,4,5-trimethoxyphenyl)ethyl}]aminoisovaleramide(Reference Compound No. 48-36)

[0729] IR(Film,cm⁻¹)3304, 3010, 2964, 2837, 1672, 1650, 1594, 1552,1504, 1454

[0730](2RS)-2-[N-Methoxyacetyl-N-{2-oxo-2-(3,4,5-trimethoxyphenyl)ethyl}]aminoisovaleramide(Reference Compound No. 48-37)

[0731] IR(Film,cm⁻¹)3304, 2964, 2830, 1666, 1591, 1552, 1504, 1462

[0732](2RS)-2-[N-Acetyl-N-{2-(3,4-dimethoxyphenyl)-2-oxoethyl}]aminoisovaleramide(Reference Compound No. 48-38)

[0733] IR(Film,cm⁻¹)3325, 2964, 2839, 1684, 1636, 1596, 1516, 1464

[0734](2RS)-2-[N-Benzoyl-N-{2-(3,4-dimethoxyphenyl)-2-oxoethyl}]aminoisovaleramide(Reference Compound No. 48-39)

[0735] IR(Film,cm⁻¹)3325, 3010, 2963, 2838, 1676, 1636, 1600, 1516, 1448

[0736](2RS)-2-[N-{2-(3,4-Dimethoxyphenyl)-2-oxoethyl}-N-methoxyacetyl]aminoisovaleramide(Reference Compound No. 48-40)

[0737] IR(Film,cm⁻¹)3326, 2964, 2936, 2836, 1670, 1596, 1516, 1464

[0738](2RS)-2-[N-Benzoyl-N-{2-(3-methoxyphenyl)-2-oxoethyl}]aminoisovaleramide(Reference Compound No. 48-41)

[0739](2RS)-2-{N-Methoxyacetyl-N-(2-oxo-2-phenylethyl)}aminoisovaleramide(Reference Compound No. 48-42)

[0740] (2RS)-2-{N-Benzoyl-N-(2-oxo-2-phenylethyl)}aminoisovaleramide(Reference Compound No. 48-43)

[0741](2R)-2-{N-(2-Oxo-2-phenylethyl)-N-(2-pyridylcarbonyl)}aminoisovaleramide(Reference Compound No. 48-44)

[0742](2R)-2-{N-(2-Oxo-2-phenylethyl)-N-(3-pyridylcarbonyl)}aminoisovaleramide(Reference Compound No. 48-45)

[0743](2R)-2-{N-(2-Oxo-2-phenylethyl)-N-(4-pyridylcarbonyl)}aminoisovaleramide(Reference Compound No. 48-46)

[0744] IR(Film,cm⁻¹)3204, 1650, 1552, 1494, 1448

[0745](2R)-2-[N-Acetyl-N-{2-(3-methoxyphenyl)-2-oxoethyl}]aminoisovaleramide(Reference Compound No. 48-47)

Reference Example 49

[0746](3RS)-4-Acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazine(Reference Compound No. 49-1)

[0747] p-Toluenesulfonic acid monohydrate (catalytic amount) is added toa solution of(2RS)-2-{N-acetyl-N-(2-oxo-2-phenylethyl)}aminoisovaleramide (900 mg,Reference Compound No. 48-1) in toluene (15 ml), and the mixture isrefluxed overnight. The reaction mixture is allowed to stand at roomtemperature, washed with a saturated aqueous sodium hydrogencarbonatesolution and saturated brine successively and dried over anhydrousmagnesium sulfate. The reaction mixture is concentrated under reducedpressure, and the resulting residue is purified by silica gel columnchromatography to give the titled reference Compound (757 mg).

[0748] mp 181.5-185.0° C.

[0749] IR(KBr,cm⁻¹)3231, 1698, 1626, 1503

[0750] The following compounds are obtained by a method similar toReference Example 49.

[0751](3R)-4-Acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazine(Reference Compound No. 49-2)

[0752] mp 152.0-157.5° C.

[0753] [α]_(D) ²⁰ −483.6° (c=1.0, methanol)

[0754] IR(KBr,cm⁻¹)3184, 3085, 2971, 2931, 1957, 1887, 1694, 1644, 1468

[0755](3S)-4-Acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazine(Reference Compound No. 49-3)

[0756] mp 151.5-155.5° C.

[0757] [α]_(D) ²⁰ +470.2° (c=0.99, methanol)

[0758] IR(KBr,cm⁻¹)3186, 3082, 2971, 2932, 1959, 1887, 1696, 1644, 1468,1444

[0759] 4-Acetyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazine (ReferenceCompound No. 49-4)

[0760] 4-Acetyl-3,3-dimethyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazine(Reference Compound No. 49-5)

[0761] mp 160.0-195.0° C.

[0762] IR(KBr,cm⁻¹)3190, 3088, 1694, 1674, 1509, 1478, 1460, 1445

[0763] (3RS)-4-Acetyl-3-ethyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazine(Reference Compound No. 49-6)

[0764] mp 181.0-185.0° C.

[0765] IR(KBr,cm⁻¹)3184, 3088, 1874, 1652, 1446

[0766](3RS)-4-Acetyl-3-{(1RS)-1-methylpropyl}-6-phenyl-1,2,3,4-tetrahydropyrazine(Reference Compound No. 49-7)

[0767] mp 176.0-177.0° C.

[0768] IR(KBr,cm⁻¹)3200, 3088, 1686, 1648, 1452

[0769](3RS)-4-Acetyl-3-isobutyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazine(Reference Compound No. 49-8)

[0770] mp 165.0-173.5° C.

[0771] IR(KBr,cm⁻¹)3196, 3088, 1689, 1674, 1649, 1470

[0772](3RS)-4-Acetyl-3-cyclohexyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazine(Reference Compound No. 49-9)

[0773] mp 226.5-228.5° C.

[0774] IR(KBr,cm⁻¹)3195, 3088, 1679, 1647, 1504, 1470, 1449

[0775](3RS)-4-Acetyl-3-{(1RS)-1-tert-butyldimethylsilyloxyethyl}-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazine(Reference Compound No. 49-10)

[0776] IR(Film,cm⁻¹)3222, 3109, 1683, 1463, 1446

[0777](3RS)-4-Acetyl-3-methoxymethyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazine(Reference Compound No. 49-11)

[0778] IR(Film,cm⁻¹)3230, 3110, 1684, 1654, 1558, 1540, 1447

[0779](3RS)-4-Acetyl-3-(2-methoxyethyl)-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazine(Reference Compound No. 49-12)

[0780] IR(Film,cm⁻¹)3223, 3109, 1682, 1651, 1446

[0781] (3RS)-4-Acetyl-3,6-diphenyl-2-oxo-1,2,3,4-tetrahydropyrazine(Reference Compound No. 49-13)

[0782] mp 180° C.

[0783] IR(KBr,cm⁻¹)3196, 3095, 1683, 1668, 1656, 1467, 1448

[0784](3RS)-4-Formyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazine(Reference Compound No. 49-14)

[0785] IR(Film,cm⁻¹)3229, 3102, 2967, 1680, 1643

[0786](3RS)-4-Isobutyryl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazine(Reference Compound No. 49-15)

[0787] IR(KBr,cm⁻¹)3219, 3112, 1680, 1642, 1468

[0788](3R)-4-Isobutyryl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4tetrahydropyrazine(Reference Compound No. 49-16)

[0789] [α]_(D) ²⁰ −401.60 (c=0.51, methanol)

[0790] IR(Film,cm⁻¹)3218, 3104, 1682, 1467, 1446

[0791](3RS)-3-Isopropyl-2-oxo-6-phenyl-4-pivaloyl-1,2,3,4-tetrahydropyrazine(Reference Compound No. 49-17)

[0792] mp 158.3-167.3° C.

[0793] IR(KBr,cm⁻¹)3191, 3087, 2970, 2932, 1679, 1639, 1473

[0794](3RS)-4-Cyclohexylcarbonyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazine(Reference Compound No. 49-18)

[0795] mp 209.1-211.4° C.

[0796] IR(KBr,cm⁻¹)3212, 3110, 2924, 2859, 1676, 1643, 1601, 1473, 1446

[0797](3RS)-3-Isopropyl-4-methoxycarbonyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazine(Reference Compound No. 49-19)

[0798] mp 117.5-127.5° C.

[0799] IR(KBr,cm⁻¹)3188, 2962, 1725, 1670, 1443

[0800](3RS)-4-Ethoxycarbonyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazine(Reference Compound No. 49-20)

[0801] mp 106.5-108.5° C.

[0802] IR(KBr,cm⁻¹)3192, 3088, 2961, 2933, 1719, 1673, 1479

[0803](3R)-3-Isopropyl-4-methoxyacetyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazine(Reference Compound No. 49-21)

[0804] [α]_(D) ²⁰ −379.30 (c=1.3, methanol)

[0805] IR(Film,cm⁻¹)3230, 3109, 2965, 2932, 2823, 1686, 1655, 1601,1465, 1447

[0806](3R)-4-Benzoyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazine(Reference Compound No. 49-22)

[0807] [α]_(D) ²⁰ −430.2° (c=1.0, methanol)

[0808] IR(Film,cm⁻¹)3216, 3102, 2966, 1683, 1642, 1600, 1578, 1464, 1447

[0809](3RS)-4-(4-Chlorobenzoyl)-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazine(Reference Compound No. 49-23)

[0810] mp 175.0-186.0° C.

[0811] IR(KBr,cm⁻¹)3852, 1680, 1646, 1590

[0812](3RS)-3-Isopropyl-4-(4-methoxybenzoyl)-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazine(Reference Compound No. 49-24)

[0813] mp 202.1-206.6° C.

[0814] IR(KBr,cm⁻¹)3855, 1676, 1643, 1601

[0815](3RS)-3-Isopropyl-4-(4-nitrobenzoyl)-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazine(Reference Compound No. 49-25)

[0816] mp 216.4-221.0° C.

[0817] IR(KBr,cm⁻¹) 1683, 1627, 1603, 1522

[0818](3RS)-3-Isopropyl-2-oxo-6-phenyl-4-(3-phenylpropanoyl)-1,2,3,4-tetrahydropyrazine(Reference Compound No. 49-26)

[0819] IR(Film,cm⁻¹)3219, 3103, 3026, 2964, 1932, 1684, 1651, 1602

[0820](3RS)-4-Benzyloxycarbonyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazine(Reference Compound No. 49-27)

[0821] mp 122.0-124.0° C.

[0822] IR(KBr,cm⁻¹)3218, 3104, 2961, 1679, 1498

[0823](3RS)-3-Isopropyl-2-oxo-4-phenoxyacetyl-6-phenyl-1,2,3,4-tetrahydropyrazine(Reference Compound No. 49-28)

[0824] mp 166.2-171.1° C.

[0825] IR(KBr,cm⁻¹)3204, 3101, 2963, 1684, 1652, 1596, 1494

[0826](3RS)-3-Isopropyl-2-oxo-6-phenyl-4-(2-thienylcarbonyl)-1,2,3,4-tetrahydropyrazine(Reference Compound No. 49-29)

[0827] mp 139.5-155.0° C.

[0828] IR(KBr,cm⁻¹)3211, 1674, 1636

[0829](3RS)-3-Isopropyl-2-oxo-6-phenyl-4-(2-pyridylcarbonyl)-1,2,3,4-tetrahydropyrazine(Reference Compound No. 49-30)

[0830] mp 195.0-196.0° C.

[0831] IR(KBr,cm⁻¹)3300-2000, 1697, 1643

[0832](3RS)-3-Isopropyl-2-oxo-6-phenyl-4-(3-pyridylcarbonyl)-1,2,3,4-tetrahydropyrazine(Reference Compound No. 49-31)

[0833] mp 170° C.

[0834] IR(KBr,cm⁻¹)3210, 3104, 2985, 2936, 1738, 1679, 1644, 1586, 1503,1464

[0835](3RS)-3-Isopropyl-2-oxo-6-phenyl-4-(4-pyridylcarbonyl)-1,2,3,4-tetrahydropyrazine(Reference Compound No. 49-32)

[0836] mp 199.0-202.5° C.

[0837] IR(KBr,cm⁻¹)3230, 3109, 3050, 2971, 1684, 1645, 1597, 1552, 1496,1460

[0838](3RS)-3-Isopropyl-4-methanesulfonyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazine(Reference Compound No. 49-33)

[0839](3RS)-4-Benzenesulfonyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazine(Reference Compound No. 49-34)

[0840](3RS)-4-Acetyl-3-isopropyl-2-oxo-6-(3,4,5-trimethoxyphenyl)-1,2,3,4-tetrahydropyrazine(Reference Compound No. 49-35)

[0841] mp 197.4-200.4° C.

[0842] IR(KBr,cm⁻¹)3227, 3110, 2965, 2829, 1678, 1652, 1585, 1516, 1466

[0843](3RS)-4-Benzoyl-3-isopropyl-2-oxo-6-(3,4,5-trimethoxyphenyl)-1,2,3,4-tetrahydropyrazine(Reference Compound No. 49-36)

[0844] IR(Film,cm⁻¹)3219, 3102, 3011, 2965, 2936, 2840, 1683, 1644,1583, 1514, 1466

[0845](3RS)-3-Isopropyl-4-methoxyacetyl-2-oxo-6-(3,4,5-trimethoxyphenyl)-1,2,3,4-tetrahydropyrazine(Reference Compound No. 49-37)

[0846] mp 146.6-149.7° C.

[0847] IR(KBr,cm⁻¹)3208, 3094, 2971, 2874, 2824, 1700, 1678, 1662, 1583,1512, 1467

[0848](3RS)-4-Acetyl-6-(3,4-dimethoxyphenyl)-3-isopropyl-2-oxo-1,2,3,4-tetrahydropyrazine(Reference Compound No. 49-38)

[0849] IR(Film,cm⁻¹)3221, 3105, 3011, 2965, 2935, 2838, 1683, 1650,1522, 1466

[0850](3RS)-4-Benzoyl-6-(3,4-dimethoxyphenyl)-3-isopropyl-2-oxo-1,2,3,4-tetrahydropyrazine(Reference Compound No. 49-39)

[0851] mp 135.0° C.

[0852] IR(KBr,cm⁻¹)3228, 3169, 2963, 2872, 1679, 1643, 1599, 1534, 1490,1466, 1442

[0853](3RS)-6-(3,4-Dimethoxyphenyl)-3-isopropyl-4-methoxyacetyl-2-oxo-1,2,3,4-tetrahydropyrazine(Reference Compound No. 49-40)

[0854] mp 137.0-140.2° C.

[0855] IR(KBr,cm⁻¹)3209, 3096, 2963, 2831, 1674, 1648, 1586, 1526, 1470

[0856](3RS)-4-Benzoyl-3-isopropyl-6-(3-methoxyphenyl)-2-oxo-1,2,3,4-tetrahydropyrazine(Reference Compound No. 49-41)

[0857](3RS)-3-Isopropyl-4-methoxyacetyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazine(Reference Compound No. 49-42)

[0858](3RS)-4-Benzoyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazine(Reference Compound No. 49-43)

[0859](3R)-3-Isopropyl-2-oxo-6-phenyl-4-(2-pyridylcarbonyl)-1,2,3,4-tetrahydropyrazine(Reference Compound No. 49-44)

[0860](3R)-3-Isopropyl-2-oxo-6-phenyl-4-(3-pyridylcarbonyl)-1,2,3,4-tetrahydropyrazine(Reference Compound No. 49-45)

[0861](3R)-3-Isopropyl-2-oxo-6-phenyl-4-(4-pyridylcarbonyl)-1,2,3,4-tetrahydropyrazine(Reference Compound No. 49-46)

[0862](3R)-4-Acetyl-3-isopropyl-6-(3-methoxyphenyl)-2-oxo-1,2,3,4-tetrahydropyrazine(Reference Compound No. 49-47)

Reference Example 50

[0863] Ethyl{(3RS)-4-acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazine-1-yl}acetate(Reference Compound No. 50-1)

[0864] Under ice cooling, 60% sodium hydride (27.9 mg) is added to asolution of(3RS)-4-acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazine(150 mg, Reference Compound No. 49-1) in tetrahydrofuran (1 ml), and themixture is stirred for 30 minutes. Ethyl bromoacetate (77 μl) is addedto the mixture, then the temperature is raised to room temperature, andthe whole is stirred for one hour. The reaction mixture is diluted withethyl acetate, and a saturated aqueous ammonium chloride solution isadded thereto. The diluted solution is washed with 0.1 N hydrochloricacid, a saturated aqueous sodium hydrogencarbonate solution andsaturated brine successively and dried over anhydrous magnesium sulfate.The diluted solution is concentrated under reduced pressure, and theresulting residue is purified by silica gel column chromatography togive the titled reference Compound (195 mg).

[0865] mp 96.0-98.0° C.

[0866] IR(KBr,cm⁻¹) 1751, 1686, 1666, 1645, 1576

[0867] The following compounds are obtained by a method similar toReference Example 50.

[0868] Ethyl{(3R)-4-acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}acetate(Reference Compound No. 50-2)

[0869] mp 115.7-118.0° C.

[0870] [α]_(D) ²⁰ 186.00 (c=1.0, methanol)

[0871] IR(KBr,cm⁻¹)3083, 2966, 2905, 2877, 1, 753, 1688, 1666, 1643

[0872] Ethyl{(3S)-4-acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}acetate(Reference Compound No. 50-3)

[0873] mp 114.5-117.5° C.

[0874] [α]_(D) ²⁰ +181.70 (c=1.0, methanol)

[0875] IR(KBr,cm⁻¹)3083, 2966, 2905, 2877, 1753, 1689, 1668, 1644

[0876] Methyl(4-acetyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl)-acetate(Reference Compound No. 50-4)

[0877] IR(KBr,cm⁻¹) 1751, 1680

[0878] Ethyl(4-acetyl-3,3-dimethyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl)acetate(Reference Compound No. 50-5)

[0879] IR(Film,cm⁻¹)1749, 1681, 1549, 1446

[0880] Ethyl{(3RS)-4-acetyl-3-ethyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}acetate (Reference Compound No. 50-6)

[0881] mp 126.0-128.0° C.

[0882] IR(KBr,cm⁻¹) 1745, 1733, 1669, 1687, 1648, 1574, 1480

[0883] Ethyl[(3RS)-4-acetyl-3-{(1RS)-1-methylpropyl}-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl]acetate(Reference Compound No. 50-7)

[0884] IR(Film,cm⁻¹) 1749, 1682, 1446

[0885] Methyl{(3RS)-4-acetyl-3-isobutyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}acetate(Reference Compound No. 50-8)

[0886] mp 127.5-134.0° C.

[0887] IR(KBr,cm⁻¹)3105, 1745, 1684, 1668, 1647, 1401

[0888] Ethyl{(3RS)-4-acetyl-3-cyclohexyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}acetate(Reference Compound No. 50-9)

[0889] mp 121.0-123.0° C.

[0890] IR(KBr,cm⁻¹)3082, 1751, 1685, 1666, 1644, 1448

[0891] Ethyl[(3RS)-4-acetyl-3-{(1RS)-1-tert-butyldimethylsilyloxyethyl}-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl]acetate(Reference Compound No. 50-10)

[0892] IR(KBr,cm⁻¹)1750, 1691, 1472

[0893] Ethyl{(3RS)-4-acetyl-3-methoxymethyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}acetate(Reference Compound No. 50-11)

[0894] IR(Film,cm⁻¹) 1749, 1684, 1446

[0895] Ethyl{(3RS)-4-acetyl-3-(2-methoxyethyl)-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}acetate(Reference Compound No. 50-12)

[0896] IR(Film,cm⁻¹)1748, 1682, 1446

[0897] Ethyl{(3RS)-4-acetyl-3,6-diphenyl-2-oxo-1,2,3,4-tetrahydropyrazin-1-yl}acetate(Reference Compound No. 50-13)

[0898] mp 144.7-147.9° C.

[0899] IR(Film,cm⁻¹)3086, 3054, 1740, 1694, 1678, 1650, 1446

[0900] Ethyl{(3RS)-4-formyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}acetate(Reference Compound No. 50-14)

[0901] IR(Film,cm⁻¹)2966, 1748, 1690, 1467, 1446

[0902] Methyl{(3RS)-4-isobutyryl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4tetrahydropyrazin-1-yl}acetate(Reference Compound No. 50-15)

[0903] IR(Film,cm⁻¹) 1755, 1685, 1652

[0904] Ethyl{(3R)-4-isobutyryl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4tetrahydropyrazin-1-yl}acetate(Reference Compound No. 50-16)

[0905] mp 69.5-74.0° C.

[0906] [α]_(D) ²⁰ −165.5° (c=0.52, methanol)

[0907] IR(KBr,cm⁻¹)1755, 1684, 1455

[0908] Ethyl{(3RS)-3-isopropyl-2-oxo-6-phenyl-4-pivaloyl-1,2,3,4-tetrahydropyrazin-1-yl}acetate(Reference Compound No. 50-17)

[0909] IR(Film,cm⁻¹)2968, 2935, 2874, 1751, 1691, 1667, 1642

[0910] Ethyl{(3RS)-4-cyclohexylcarbonyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}acetate(Reference Compound No. 50-18)

[0911] mp 125.6-128.6° C.

[0912] IR(KBr,cm⁻¹)2934, 2861, 1749, 1686, 1667, 1645, 1470, 1450

[0913] Methyl{(3RS)-3-isopropyl-4-methoxycarbonyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}acetate(Reference Compound No. 50-19)

[0914] IR(Film,cm⁻¹)2960, 1755, 1720, 1692, 1445

[0915] Methyl{(3RS)-4-ethoxycarbonyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}acetate(Reference Compound No. 50-20)

[0916] IR(File,cm⁻¹)2964, 1755, 1714, 1693

[0917] Ethyl{(3R)-3-isopropyl-4-methoxyacetyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}acetate(Reference Compound No. 50-21)

[0918] [α]_(D) ²⁰ −150.1 (c=1.0, methanol)

[0919] IR(KBr,cm⁻¹)2965, 2824, 1749, 1690, 1657

[0920] Ethyl{(3R)-4-benzoyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}acetate(Reference Compound No. 50-22)

[0921] mp 110.0-116.8° C.

[0922] [α]_(D) ²⁰ −211.5° (c=1.0, methanol)

[0923] IR(KBr,cm⁻¹)3108, 3059, 3030, 2968, 1747, 1672, 1647, 1600, 1579,1492

[0924] Methyl{(3RS)-4-(4-chlorobenzoyl)-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}acetate(Reference Compound No. 50-23)

[0925] mp 125.5-128.0° C.

[0926] IR(KBr,cm⁻¹)1753, 1685, 1636, 1590

[0927] Methyl{(3RS)-3-isopropyl-4-(4-methoxybenzoyl)-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}acetate(Reference Compound No. 50-24)

[0928] mp 179.6-185.8° C.

[0929] IR(KBr,cm⁻¹) 1744, 1683, 1651, 1630, 1607

[0930] Methyl{(3RS)-3-isopropyl-4-(4-nitrobenzoyl)-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}acetate(Reference Compound No. 50-25)

[0931] mp 162.0-165.5° C.

[0932] IR(KBr,cm⁻¹)1760, 1688, 1638, 1600, 1524

[0933] Ethyl{(3RS)-3-isopropyl-2-oxo-6-phenyl-4-(3-phenylpropanoyl)-1,2,3,4-tetrahydropyrazin-1-yl}acetate(Reference Compound No. 50-26)

[0934] mp 131.7-134.0° C.

[0935] IR(KBr,cm⁻¹)3086, 3032, 2967, 2941, 1745, 1669, 1645, 1600, 1577

[0936] Methyl{(3RS)-4-benzyloxycarbonyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}acetate(Reference Compound No. 50-27)

[0937] IR(Film,cm⁻¹)3032, 2963, 1755, 1714, 1692, 1446

[0938] Ethyl{(3RS)-3-isopropyl-2-oxo-4-phenoxyacetyl-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}acetate(Reference Compound No. 50-28)

[0939] mp 133.8-137.3° C.

[0940] IR(KBr,cm⁻¹)3058, 2978, 1759, 1680, 1598, 1497

[0941] Methyl{(3RS)-3-isopropyl-2-oxo-6-phenyl-4-(2-thienylcarbonyl)-1,2,3,4-tetrahydropyrazin-1-yl}acetate(Reference Compound No. 50-29)

[0942] IR(Film,cm⁻¹)2962, 1752, 1690, 1630, 1516

[0943] Methyl{(3RS)-3-isopropyl-2-oxo-6-phenyl-4-(2-pyridylcarbonyl)-1,2,3,4-tetrahydropyrazin-1-yl}acetate(Reference Compound No. 50-30)

[0944] IR(Film,cm⁻¹) 1753, 1688, 1600

[0945] tert-Butyl{(3RS)-3-isopropyl-2-oxo-6-phenyl-4-(3-pyridylcarbonyl)-1,2,3,4-tetrahydropyrazin-1-yl}acetate(Reference Compound No. 50-31)

[0946] IR(Film,cm⁻¹)2972, 2934, 2875, 1741, 1690, 1671, 1648, 1588,1467, 1446

[0947] tert-Butyl{(3RS)-3-isopropyl-2-oxo-6-phenyl-4-(4-pyridylcarbonyl)-1,2,3,4-tetrahydropyrazin-1-yl}acetate(Reference Compound No. 50-32)

[0948] IR(Film,cm⁻¹)2971, 1741, 1688, 1651, 1596, 1550, 1447

[0949] Ethyl{(3RS)-3-isopropyl-4-methanesulfonyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}acetate(Reference Compound No. 50-33)

[0950] IR(Film,cm⁻¹)2967, 2934, 2875, 1747, 1690, 1492, 1467

[0951] Methyl{(3RS)-4-benzenesulfonyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}acetate(Reference Compound No. 50-34)

[0952] IR(Film,cm⁻¹)3062, 2968, 2875, 1749, 1691, 1468, 1449

[0953] Ethyl{(3RS)-4-acetyl-3-isopropyl-2-oxo-6-(3,4,5-trimethoxyphenyl)-1,2,3,4-tetrahydropyrazin-1-yl}acetate(Reference Compound No. 50-35)

[0954] mp 129.8-134.2° C.

[0955] IR(KBr,cm⁻¹)3083, 2962, 2887, 2838, 1738, 1692, 1668, 1587, 1509,1458

[0956] Ethyl{(3RS)-4-benzoyl-3-isopropyl-2-oxo-6-(3,4,5-trimethoxyphenyl)-1,2,3,4-tetrahydropyrazin-1-yl}acetate(Reference Compound No. 50-36)

[0957] mp 161.0-165.4° C.

[0958] IR(KBr,cm⁻¹)3097, 2981,2957, 2826, 1749, 1670, 1648, 1586, 1559,1540, 1508, 1490, 1458

[0959] Ethyl{(3RS)-3-isopropyl-4-methoxyacetyl-2-oxo-6-(3,4,5-trimethoxyphenyl)-1,2,3,4-tetrahydropyrazin-1-yl}acetate(Reference Compound No. 50-37)

[0960] IR(Film,cm⁻¹)2964, 2828, 1748, 1691, 1582, 1540, 1507, 1464

[0961] Ethyl{(3RS)-4-acetyl-6-(3,4-dimethoxyphenyl)-3-isopropyl-2-oxo-1,2,3,4-tetrahydropyrazin-1-yl}acetate(Reference Compound No. 50-38)

[0962] IR(Film,cm⁻¹)2965, 2937, 2838, 1748, 1682, 1653, 1603, 1582,1517, 1465

[0963] Ethyl{(3RS)-4-benzoyl-6-(3,4-dimethoxyphenyl)-3-isopropyl-2-oxo-1,2,3,4-tetrahydropyrazin-1-yl}acetate(Reference Compound No. 50-39)

[0964] mp 147.7-149.8° C.

[0965] IR(KBr,cm⁻¹)3086, 2965, 2938, 2874, 2842, 1746, 1669, 1648, 1602,1583, 1519, 1493, 1465, 1449

[0966] Ethyl{(3RS)-6-(3,4-dimethoxyphenyl)-3-isopropyl-4-methoxyacetyl-2-oxo-1,2,3,4-tetrahydropyrazin-1-yl}acetate(Reference Compound No. 50-40)

[0967] IR(Film,cm⁻¹)2964, 2936, 2837, 1747, 1689, 1657, 1603, 1582,1547, 1517,

[0968] Ethyl{(3RS)-4-benzoyl-3-isopropyl-6-(3-methoxyphenyl)-2-oxo-1,2,3,4-tetrahydropyrazin-1-yl}acetate(Reference Compound No. 50-41)

[0969] IR(KBr,cm⁻¹)3083, 3057, 2962, 1755, 1667, 1643, 1600, 1496, 1226

[0970] Ethyl{(3RS)-3-isopropyl-4-methoxyacetyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}acetate(Reference Compound No. 50-42)

[0971] Ethyl{(3RS)-4-benzoyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}acetate(Reference Compound No. 50-43)

[0972] mp 123.0-124.0° C.

[0973] IR(KBr,cm⁻¹)3103, 3059, 2957, 2890, 2870, 1752, 1672, 1645, 1492

[0974] tert-Butyl{(3R)-3-isopropyl-2-oxo-6-phenyl-4-(2-pyridylcarbonyl)-1,2,3,4-tetrahydropyrazin-1-yl}acetate(Reference Compound No. 50-44)

[0975] mp 113.9-117.0° C.

[0976] IR(KBr,cm⁻¹)2971, 2930, 1753, 1691, 1669, 1640, 1439

[0977] tert-Butyl{(3R)-3-isopropyl-2-oxo-6-phenyl-4-(3-pyridylcarbonyl)-1,2,3,4-tetrahydropyrazin-1-yl}acetate(Reference Compound No. 50-45)

[0978] IR(Film,cm⁻¹)2972, 2930, 1742, 1690, 1674, 1649, 1387, 1230,1155, 756, 702

[0979] tert-Butyl{(3R)-3-isopropyl-2-oxo-6-phenyl-4-(4-pyridylcarbonyl)-1,2,3,4-tetrahydropyrazin-1-yl}acetate(Reference Compound No. 50-46)

[0980] IR(Film,cm⁻¹)1741, 1690, 1388, 1230, 1155, 756

[0981] Ethyl{(3R)-4-acetyl-3-isopropyl-6-(3-methoxyphenyl)-2-oxo-1,2,3,4-tetrahydropyrazin-1-yl}acetate(Reference Compound No. 50-47)

[0982] [α]_(D) ²⁰ −173.2° (c=1.0, methanol)

[0983] IR(Film,cm⁻¹)1752, 1684, 1599, 1579

Reference Example 51

[0984]{(3RS)-4-Acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}aceticAcid (Reference Compound No. 51-1)

[0985] A 4 N aqueous lithium hydroxide solution (0.4 ml) is added to asolution of ethyl{(3RS)-4-acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}acetate(185 mg, Reference Compound No. 50-1) in ethanol (5 ml), and the mixtureis stirred for 35 minutes. To the reaction mixture is added 1 Nhydrochloric acid to acidify the system, and the whole is extracted withethyl acetate. The extract is washed with saturated brine and dried overanhydrous magnesium sulfate. The extract is concentrated under reducedpressure to give the titled reference Compound (167 mg).

[0986] IR(Film,cm⁻¹)3400-2000, 1743, 1691, 1640, 1495, 1446

[0987] The following compounds are obtained by a method similar toReference Example 51.

[0988]{(3R)-4-Acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}aceticAcid (Reference Compound No. 51-2)

[0989] [α]_(D) ²⁰ +186.60 (c=1.0, methanol)

[0990] IR(Film,cm⁻¹)3450, 2968, 1725, 1681, 1617

[0991]{(3S)-4-Acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}aceticAcid (Reference Compound No. 51-3)

[0992] [α]_(D) ²⁰ −178.9° (c=1.0, methanol)

[0993] IR(Film,cm⁻¹)2966, 2606, 1742, 1683, 1467, 1447

[0994] (4-Acetyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl)aceticAcid (Reference Compound No. 51-4)

[0995] mp 210° C.

[0996] IR(KBr,cm⁻¹)3250-2500, 1739, 1684, 1665, 1614

[0997](4-Acetyl-3,3-dimethyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl)aceticacid (Reference Compound No. 51-5)

[0998] IR(Film,cm⁻¹)3016, 1676, 1558, 1385

[0999]{(3RS)-4-Acetyl-3-ethyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}aceticacid (Reference Compound No. 51-6)

[1000] mp 203.5-206.0° C.

[1001] IR(KBr,cm⁻¹) 1748, 1674, 1624, 1450

[1002][(3RS)-4-Acetyl-3-{(1RS)-1-methylpropyl}-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl]aceticAcid (Reference Compound No. 51-7)

[1003] IR(KBr,cm⁻¹) 1742, 1683, 1395{(3RS)-4-Acetyl-3-isobutyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}aceticAcid (Reference Compound No. 51-8)

[1004] IR(Film,cm⁻¹)1742, 1687, 1393{(3RS)-4-Acetyl-3-cyclohexyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}aceticAcid (Reference Compound No. 51-9)

[1005] IR(KBr,cm⁻¹) 1743, 1688, 1448

[1006][(3RS)-4-Acetyl-3-{(1RS)-1-tert-butyldimethylsilyloxyethyl}-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl]aceticAcid (Reference Compound No. 51-10)

[1007] mp 92.0-101.0° C.

[1008] IR(KBr,cm⁻¹)1745, 1677, 1628, 1404

[1009]{(3RS)-4-Acetyl-3-methoxymethyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}aceticAcid (Reference Compound No. 51-11)

[1010] IR(Film,cm⁻¹)3015, 1741, 1686, 1657, 1492, 1447

[1011]{(3RS)-4-Acetyl-3-(2-methoxyethyl)-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}aceticAcid (Reference Compound No. 51-12)

[1012] mp 107.5-118.0° C.

[1013] IR(KBr,cm⁻¹)1740, 1684, 1646, 1497, 1487

[1014]{(3RS)-4-Acetyl-3,6-diphenyl-2-oxo-1,2,3,4-tetrahydropyrazin-1-yl}aceticacid (Reference Compound No. 51-13)

[1015] IR(Film,cm⁻¹)3022, 1738, 1682, 1495, 1447

[1016]{(3RS)-4-Isobutyryl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}aceticAcid (Reference Compound No. 51-14)

[1017] IR(KBr,cm⁻¹)3500-2500, 1748, 1690, 1470, 1448

[1018]{(3R)-4-Isobutyryl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}aceticAcid (Reference Compound No. 51-15)

[1019] [α]_(D) ²⁰ −158.8° (c=0.53, methanol)

[1020] IR(KBr,cm⁻¹)3500-2800, 1744, 1687

[1021]{(3RS)-3-Isopropyl-2-oxo-6-phenyl-4-pivaloyl-1,2,3,4-tetrahydropyrazin-1-yl}aceticAcid (Reference Compound No. 51-16)

[1022] IR(Film,cm⁻¹)2968, 1745, 1690, 1664, 1446

[1023]{(3RS)-4-Cyclohexylcarbonyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}aceticAcid (Reference Compound No. 51-17)

[1024] IR(Film,cm⁻¹)3410, 2933, 2856, 1685, 1674, 1646, 1558, 1540,1506, 1496, 1447

[1025]{(3RS)-3-Isopropyl-4-methoxycarbonyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}aceticAcid (Reference Compound No. 51-18)

[1026] mp 159.0-162.0° C.

[1027] IR(KBr,cm⁻¹)2969, 1745, 1710, 1616, 1448

[1028]{(3RS)-4-Ethoxycarbonyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}aceticAcid (Reference Compound No. 51-19)

[1029] mp 172.3-174.5° C.

[1030] IR(KBr,cm⁻¹)2983, 2938, 1751, 1711, 1661, 1629

[1031]{(3R)-3-Isopropyl-4-methoxyacetyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}aceticAcid (Reference Compound No. 51-20)

[1032] [α]_(D) ²⁰ −95.8 (c=0.99, methanol)

[1033] IR(Film,cm⁻¹)3500, 2966, 1742, 1686, 1653, 1447

[1034]{(3R)-4-Benzoyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}aceticAcid (Reference Compound No. 51-21)

[1035] [α]_(D) ²⁰ −221.9° (c=1.0, methanol)

[1036] IR(KBr,cm⁻¹)3087, 2960, 1746, 1670, 1605, 1572, 1492, 1448z{(3RS)-4-(4-Chlorobenzoyl)-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}aceticAcid (Reference Compound No. 51-22)

[1037] mp 181.5-183.5° C.

[1038] IR(KBr,cm⁻¹)3150, 1751, 1692, 1668, 1626z{(3RS)-3-Isopropyl-4-(4-methoxybenzoyl)-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}aceticAcid (Reference Compound No. 51-23)

[1039] mp 186.5-188.0° C.

[1040] IR(KBr,cm⁻¹)3500-2200, 1737, 1688, 1611

[1041]{(3RS)-3-Isopropyl-4-(4-nitrobenzoyl)-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}aceticAcid (Reference Compound No. 51-24)

[1042] mp 186.5-188.0° C.

[1043] IR(Film,cm⁻¹)3500-2200, 1737, 1688, 1611

[1044]{(3RS)-3-Isopropyl-2-oxo-6-phenyl-4-(3-phenylpropanoyl)-1,2,3,4-tetrahydropyrazin-1-yl}aceticAcid (Reference Compound No. 51-25)

[1045] IR(Film,cm⁻¹)2963, 1742, 1685, 1549, 1448{(3RS)-4-Benzyloxycarbonyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}aceticAcid (Reference Compound No. 51-26)

[1046] mp 182.0-192.0° C.

[1047] IR(KBr,cm⁻¹)2966, 2725, 1754, 1713, 1625, 1448

[1048]{(3RS)-3-Isopropyl-2-oxo-4-phenoxyacetyl-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}aceticAcid (Reference Compound No. 51-27)

[1049]{(3RS)-3-Isopropyl-2-oxo-6-phenyl-4-(2-thienylcarbonyl)-1,2,3,4-tetrahydropyrazin-1-yl}aceticAcid (Reference Compound No. 51-28)

[1050] IR(Film,cm⁻¹)2966, 1745, 1692, 1632, 1516, 1446

[1051]{(3RS)-3-Isopropyl-2-oxo-6-phenyl-4-(2-pyridylcarbonyl)-1,2,3,4-tetrahydropyrazin-1-yl}aceticAcid (Reference Compound No. 51-29)

[1052] IR(Film,cm⁻¹)3500-2200, 1734, 1684

[1053]{(3RS)-3-Isopropyl-4-methanesulfonyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}aceticAcid (Reference Compound No. 51-30)

[1054] IR(Film,cm⁻¹)3400-2750, 1748, 1660, 1636, 1447

[1055]{(3RS)-4-Benzenesulfonyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}aceticAcid (Reference Compound No. 51-31)

[1056] IR(Film,cm⁻¹)3400-2750, 1748, 1660, 1636, 1447

[1057]{(3RS)-4-Acetyl-3-isopropyl-2-oxo-6-(3,4,5-trimethoxyphenyl)-1,2,3,4-tetrahydropyrazin-1-yl}aceticAcid (Reference Compound No. 51-32)

[1058] IR(Film,cm⁻¹)2966, 1688, 1583, 1507, 1463

[1059]{(3RS)-4-Benzoyl-3-isopropyl-2-oxo-6-(3,4,5-trimethoxyphenyl)-1,2,3,4-tetrahydropyrazin-1-yl}aceticAcid (Reference Compound No. 51-33)

[1060] mp 240.0° C.

[1061] IR(KBr,cm⁻¹)3515, 2969, 1664, 1585, 1508, 1465

[1062]{(3RS)-3-Isopropyl-4-methoxyacetyl-2-oxo-6-(3,4,5-trimethoxyphenyl)-1,2,3,4-tetrahydropyrazin-1-yl}aceticAcid (Reference Compound No. 51-34)

[1063] IR(Film,cm⁻¹)2968, 2831, 1688, 1649, 1584, 1503, 1464

[1064]{(3RS)-4-Acetyl-6-(3,4-dimethoxyphenyl)-3-isopropyl-2-oxo-1,2,3,4-tetrahydropyrazin-1-yl}aceticAcid (Reference Compound No. 51-35)

[1065] IR(Film,cm⁻¹)3019, 2967, 1736, 1686, 1649, 1632, 1517, 1465

[1066]{(3RS)-4-Benzoyl-6-(3,4-dimethoxyphenyl)-3-isopropyl-2-oxo-1,2,3,4-tetrahydropyrazin-1-yl}aceticAcid (Reference Compound No. 51-36)

[1067] IR(Film,cm⁻¹)3018, 2965, 2840, 1742, 1689, 1666, 1644, 1601,1578, 1517, 1464, 1447

[1068]{(3RS)-6-(3,4-Dimethoxyphenyl)-3-isopropyl-4-methoxyacetyl-2-oxo-1,2,3,4-tetrahydropyrazin-1-yl}aceticAcid (Reference Compound No. 51-37)

[1069] IR(Film,cm⁻¹)2966, 2838, 1739, 1687, 1652, 1605, 1584, 1517, 1465

[1070]{(3RS)-4-Benzoyl-3-isopropyl-6-(3-methoxyphenyl)-2-oxo-1,2,3,4-tetrahydropyrazin-1-yl}aceticAcid (Reference Compound No. 51-38)

[1071]{(3RS)-3-Isopropyl-4-methoxyacetyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}aceticAcid (Reference Compound No. 51-39)

[1072]{(3RS)-4-Benzoyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}aceticAcid (Reference Compound No. 51-40)

[1073]{(3R)-3-Isopropyl-2-oxo-6-phenyl-4-(2-pyridylcarbonyl)-1,2,3,4-tetrahydropyrazin-1-yl}aceticAcid (Reference Compound No. 51-41)

[1074]{(3RS)-4-Acetyl-3-isopropyl-6-(3-methoxyphenyl)-2-oxo-1,2,3,4-tetrahydropyrazin-1-yl}aceticAcid (Reference Compound No. 51-42)

Reference Example 52

[1075] DL-N-tert-Butoxycarbonylphenylglycine (Reference Compound No.52-1)

[1076] Triethylamine (14.4 ml) and water (50 ml) are added to asuspension of DL-phenylglycine (15.1 g) in tetrahydrofuran (100 ml).Di-tert-butyl dicarbonate (22.9 g) is added to the mixture, and thewhole is stirred overnight. Diethyl ether is added to the reactionmixture, and the whole is extracted with a saturated aqueous sodiumhydrogencarbonate solution. A 10% aqueous citric acid solution is addedto the extract to acidify the system, and the whole is extracted withethyl acetate. The extract is washed with saturated brine and dried overanhydrous magnesium sulfate. The extract is concentrated under reducedpressure to give the titled reference Compound (25 g).

[1077] IR(Film,cm⁻¹)3300, 1720, 1657, 1497, 1455

Reference Example 53 DL-N-tert-Butoxycarbonylcyclohexylglycine(Reference Compound No. 53-1)

[1078]

[1079] Under a nitrogen atmosphere, 5% rhodium/alumina (3.00 g) is addedto a solution of DL-N-tert-butoxycarbonylphenylglycine in ethanol (80ml). The atmosphere is replaced with pressurized hydrogen (4.0 kgf/cm²)and stirred for ten days. The 5% rhodium/alumina is filtered out. Thefiltrate is concentrated under reduced pressure, and the residue ispurified by silica gel column chromatography to give the titledreference Compound (25.0 g).

Reference Example 54

[1080] Ethyl (2RS)-2-amino-4-methoxybutyrate hydrochloride (ReferenceCompound No. 54-1)

[1081] Sodium hydride (1.8 g) is added to a solution ofN-(diphenylmethylene)glycine ethyl ester in tetrahydrofuran under icecooling, then the temperature is raised to room temperature, and themixture is stirred for one hour. 2-Bromoethyl methyl ether (4.22 ml) isadded to the mixture, and the whole is refluxed overnight. The reactionmixture is cooled to room temperature, 0.1 N hydrochloric acid is addedthereto, and the whole is stirred for four hours. Ethyl acetate is addedto the reaction mixture, and the whole is extracted with 0.1 Nhydrochloric acid. The extract is basified with a saturated aqueoussodium hydrogencarbonate solution, and the whole is extracted with ethylacetate. The extract is washed with saturated brine and dried overanhydrous magnesium sulfate. The extract is concentrated under reducedpressure, a 4 N hydrogen chloride/ethyl acetate solution is added to theresulting residue, and the whole is concentrated under reduced pressureagain to give the titled reference compound (2.67 g).

[1082] IR(Film,cm⁻¹)3418, 1746, 1595, 1504

Reference Example 55

[1083] Methyl (2RS,3RS)-3-tert-butyldimethylsilyloxy-2-(2-oxo-2-phenylethyl)aminobutyrate(Reference Compound No. 55-1)

[1084] Diisopropylethylamine (3.1 ml) is added to a solution of methyl(2RS, 3RS)-3-hydroxy-2-(2-oxo-2-phenylethyl)aminobutyrate (3.70 g,Reference Compound No. 46-10) in methylene chloride (35 ml). The mixtureis cooled with ice, and tert-butyldimethylsilyltrifluoromethanesulfonate (4.06 ml) is added to the mixture. Then, thetemperature is raised to room temperature, and the whole is stirredovernight. Diethyl ether is added to the reaction mixture, and the wholeis washed with a saturated aqueous sodium hydrogencarbonate solution andsaturated brine successively, and the organic layer is dried overanhydrous magnesium sulfate. The organic layer is concentrated underreduced pressure, and the resulting residue is purified by silica gelcolumn chromatography to give the titled reference Compound (4.21 g).

[1085] IR(Film,cm⁻¹)3342, 3062, 1742, 1693, 1598, 1580

Reference Example 56

[1086] Methyl (2RS)-2-{N-formyl-N-(2-oxo-2-phenylethyl)}aminoisovalerate(Reference Compound No. 56-1)

[1087] Formic acid (0.46 ml) is added to a suspension of1,1′-oxalyldiimidazole in acetonitrile under ice cooling, and themixture is stirred for five minutes. The temperature is raised to roomtemperature, and the mixture is stirred for 15 minutes. Then, to themixture is added methyl (2RS)-2-(2-oxo-2-phenylethyl) aminoisovalerate(3.00 g, Reference Compound No. 46-1), and the whole is stirred for twohours. The reaction mixture is concentrated under reduced pressure, andthe resulting residue is diluted with ethyl acetate. The dilute solutionis washed with water, 0.1 N hydrochloric acid and saturated brinesuccessively and dried over anhydrous magnesium sulfate. The solution isconcentrated under reduced pressure, and the resulting residue ispurified by silica gel column chromatography to give the titledreference compound (2.60 g).

[1088] IR(Film,cm⁻¹)2965, 2875, 1740, 1703, 1677, 1598, 1582, 1449

Reference Example 57

[1089] Methyl(2RS)-2-{N-methoxycarbonyl-N-(2-oxo-2-phenylethyl)}aminoisovalerate(Reference Compound No. 57-1)

[1090] Water (4 ml) and sodium carbonate (1.87 ml) are added to asolution of methyl (2RS)-2-(2-oxo-2-phenylethyl)aminoisovalerate (2.0 g,Reference Compound No. 46-1) in ethyl acetate (20 ml). Methylchloroformate (1.12 ml) is added to the mixture, and the whole isstirred for one day. Ethyl acetate is added to the reaction mixture, thewhole is washed with water and saturated brine successively, and theorganic layer is dried over anhydrous magnesium sulfate. The organiclayer is concentrated under reduced pressure, and the resulting residueis purified by silica gel column chromatography to give the titledreference Compound (2.45 g).

[1091] IR(Film,cm⁻¹)2960, 1739, 1710, 1452

[1092] The following compounds are obtained by a method similar toReference Example 57.

[1093] Methyl(2RS)-2-{N-ethoxycarbonyl-N-(2-oxo-2-phenylethyl)}aminoisovalerate(Reference Compound No. 57-2)

[1094] IR(Film,cm⁻¹)2965, 1739, 1708, 1598, 1448

[1095] Methyl(2RS)-2-{N-benzyloxycarbonyl-N-(2-oxo-2-phenylethyl)}aminoisovalerate(Reference Compound No. 57-3)

[1096] IR(Film,cm⁻¹)2963, 1736, 1702, 1598, 1449

[1097] Methyl(2RS)-2-{N-(2-oxo-2-phenylethyl)-N-(2-thienylcarbonyl)}aminoisovalerate(Reference Compound No. 57-4)

[1098] IR(Film,cm⁻¹)2963, 1738, 1702, 1628, 1521

Reference Example 58

[1099] Methyl (2RS)-2-(N-methanesulfonyl)aminoisovalerate (ReferenceCompound No. 58-1)

[1100] Triethylamine (6.7 ml) is added to a solution of DL-valine methylester hydrochloride (3.35 g, Reference Compound No. 45-1) in methylenechloride (70 ml). The mixture is cooled with ice, methanesulfonylchloride (1.9 ml) is added to the mixture, and the whole is stirredovernight. Ethyl acetate is added to the reaction mixture, the whole iswashed with 0.1 N hydrochloric acid and saturated brine successively,and the organic layer is dried over anhydrous magnesium sulfate. Theorganic layer is concentrated under reduced pressure, and the resultingresidue is purified by silica gel column chromatography to give thetitled reference Compound (4.00 g).

[1101] IR(Film,cm⁻¹)3287, 3024, 2967, 2877, 1793

Reference Example 59

[1102] Methyl(2RS)-2-{N-methanesulfonyl-N-(2-oxo-2-phenylethyl)}aminoisovalerate(Reference Compound No. 59-1)

[1103] Sodium hydride (574 mg) is added to a solution of methyl(2RS)-2-(N-methanesulfonyl)aminoisovalerate (2.5 g, Reference CompoundNo. 58-1) in dimethylformamide (30 ml) under ice cooling, and themixture is stirred for 20 minutes. Phenacyl bromide is added to themixture, and the whole is stirred at 70° C. for two days. The reactionmixture is cooled to room temperature, and ethyl acetate is added to thereaction mixture. The whole is washed with water and saturated brinesuccessively, and the organic layer is dried over anhydrous magnesiumsulfate. The organic layer is concentrated under reduced pressure, andthe resulting residue is purified by silica gel column chromatography togive the titled reference Compound (3.00 g).

[1104] IR(Film,cm⁻¹)2968, 2877, 1740, 1703, 1598, 1581, 1450

Reference Example 60{(3RS)-4-Formyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}aceticAcid (Reference Compound No. 60-1)

[1105]

[1106] Potassium carbonate (983 mg) and water (6 ml) are added to asolution of ethyl{(3RS)-4-formyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}acetate(1.96 g, Reference compound No. 50-1) in ethanol (14 ml), and themixture is stirred overnight. Ethyl acetate is added to reactionmixture, and the whole is extracted with water. A 10% aqueous citricacid solution is added to the extract to acidify the system, and thewhole is extracted with ethyl acetate again. The extract is washed withwater and dried over anhydrous magnesium sulfate. The extract isconcentrated under reduced pressure to give the titled referenceCompound (0.90 g).

[1107] IR(Film,cm⁻¹)2967, 2608, 1684, 1447

Reference Example 61{(3RS)-3-Isopropyl-2-oxo-6-phenyl-4-(3-pyridylcarbonyl)-1,2,3,4-tetrahydropyrazin-1-yl}aceticAcid (Reference Compound No. 61-1)

[1108]

[1109] A 4 N hydrogen chloride/ethyl acetate solution (4.00 ml) is addedto tert-butyl(3RS)-3-isopropyl-2-oxo-6-phenyl-4-(3-pyridylcarbonyl)-1,2,3,4-tetrahydropyrazin-1-yl}acetate(300 mg, Reference Compound No. 50-31), and the mixture is stirred forfour hours. The reaction mixture is concentrated under reduced pressure,and the resulting residue is washed with diethyl ether/n-hexane to givethe titled reference Compound (1.29 g).

[1110] mp 230-240° C.

[1111] IR(KBr,cm⁻¹)3056, 2965, 2879, 1682, 1603, 1543, 1465, 1448

[1112] The following compounds are obtained by a method similar toReference Example 61.

[1113]{(3RS)-3-Isopropyl-2-oxo-6-phenyl-4-(4-pyridylcarbonyl)-1,2,3,4-tetrahydropyrazin-1-yl}aceticacid (Reference Compound No. 61-2)

[1114] IR(KBr,cm⁻¹)3087, 2965, 2879, 2726, 1733, 1678, 1655, 1599, 1501,1447

[1115]{(3R)-3-Isopropyl-2-oxo-6-phenyl-4-(3-pyridylcarbonyl)-1,2,3,4-tetrahydropyrazin-1-yl}aceticAcid (Reference Compound No. 61-3)

[1116]{(3R)-3-Isopropyl-2-oxo-6-phenyl-4-(4-pyridylcarbonyl)-1,2,3,4-tetrahydropyrazin-1-yl}aceticAcid (Reference Compound No. 61-4)

Reference Example 62

[1117]{(3R)-4-Acetyl-6-(3-hydroxyphenyl)-3-isopropyl-2-oxo-1,2,3,4-tetrahydropyrazin-1-yl}aceticAcid (Reference Compound No. 62-1)

[1118] A solution of{(3R)-4-acetyl-3-isopropyl-6-(3-methoxyphenyl)-2-oxo-1,2,3,4-tetrahydropyrazin-1-yl}aceticacid (1.55 g, Reference Compound No. 51-42) in methylene chloride (20ml) is cooled to −78° C., and boron tribromide (10.6 g) is added to thesolution. The temperature is raised to room temperature, then themixture is stirred for three hours, and methylene chloride and ice-coldwater are added to the reaction mixture. The whole is extracted withethyl acetate, and the extract is washed with saturated brine. Theextract is dried over anhydrous magnesium sulfate and concentrated underreduced pressure to give the titled reference Compound (1.49 g).

[1119] [α]_(D) ²⁰ −167.90 (c=0.22, methanol)

[1120] IR(Film,cm⁻¹)3500-3000, 1734, 1651

[1121] The following compounds are obtained by a method similar toReference Example 62.

[1122] {(3RS)-4-Acetyl-3-isopropyl-2-oxo-6-(3,4,5-trihydroxyphenyl)1,2,3,4-tetrahydropyrazin-1-yl}acetic Acid (Reference Compound No. 62-2)

[1123] IR(Film,cm⁻¹)3424, 1643, 1537

[1124]{(3RS)-4-Benzoyl-3-isopropyl-2-oxo-6-(3,4,5-trihydroxyphenyl)-1,2,3,4-tetrahydropyrazin-1-yl}aceticAcid (Reference Compound No. 62-3)

[1125] IR(KBr,cm⁻¹)3454, 1660, 1605, 1538, 1495, 1464

[1126]{(3RS)-4-Acetyl-6-(3,4-dihydroxyphenyl)-3-isopropyl-2-oxo-1,2,3,4-tetrahydropyrazin-1-yl}aceticAcid (Reference Compound No. 62-4)

[1127] IR(Film,cm⁻¹)3425, 1636, 1522

Reference Example 63

[1128] Benzyl{(3R)-4-acetyl-6-(3-benzyloxyphenyl)-3-isopropyl-2-oxo-1,2,3,4-tetrahydropyrazin-1-yl}acetate(Reference Compound No. 63-1)

[1129] Potassium carbonate (920 mg) and benzyl bromide (0.48 ml) areadded to a solution of{(3R)-4-acetyl-6-(3-hydroxyphenyl)-3-isopropyl-2-oxo-1,2,3,4-tetrahydropyrazin-1-yl}aceticacid (221 mg, Reference Compound No. 62-1) in acetone (10 ml). Then, thetemperature is raised to 50° C., and the mixture is stirred overnight.To the reaction mixture is added 1 N hydrochloric acid to acidify thesystem, and the whole is extracted with ethyl acetate. The extract iswashed with saturated brine and dried over anhydrous magnesium sulfate.The extract is concentrated under reduced pressure, and the resultingresidue is purified by silica gel column chromatography to give thetitled reference Compound (276 mg).

[1130] [α]_(D) ²⁰ −123.2° (c=1.0, methanol)

[1131] IR(Film,cm⁻¹) 1748, 1682

[1132] The following compounds are obtained by a method similar toReference Example 63.

[1133] 3-Chlorobenzyl[(3R)-4-acetyl-6-{3-(3-chlorobenzyloxy)phenyl}-3-isopropyl-2-oxo-1,2,3,4-tetrahydropyrazin-1-yl]acetate(Reference Compound No. 63-2)

[1134] [α]_(D) ²⁰ −113.90 (c=1.0, methanol)

[1135] IR(Film,cm⁻¹) 1752, 1682

[1136] 3,5-Dichlorobenzyl[(3R)-4-acetyl-6-{3-(3,5-dichlorobenzyloxy)-phenyl}-3-isopropyl-2-oxo-1,2,3,4-tetrahydropyrazin-1-yl]acetate(Reference Compound No. 63-3)

[1137] [α]_(D) ²⁰ −101.90 (c=0.51, methanol)

[1138] IR(Film,cm⁻¹)1755, 1682, 1652, 1593, 1570, 1436, 1386

Reference Example 64

[1139]{(3R)-4-Acetyl-6-(3-benzyloxyphenyl)-3-isopropyl-2-oxo-1,2,3,4-tetrahydropyrazin-1-yl}aceticAcid (Reference Compound No. 64-1)

[1140] A 4 N aqueous lithium hydroxide solution (1.5 ml) is added to asolution of benzyl{(3R)-4-acetyl-6-(3-benzyloxyphenyl)-3-isopropyl-2-oxo-1,2,3,4-tetrahydropyrazin-1-yl}acetate(276 mg, Reference Compound No. 63-1) in ethanol (8 ml)/diethyl ether (2ml), and the mixture is stirred overnight. To the reaction mixture isadded 6 N hydrochloric acid to acidify the system, and the whole isextracted with ethyl acetate. The extract is washed with saturatedbrine, dried over anhydrous magnesium sulfate and concentrated underreduced pressure to give the titled reference Compound (215 mg).

[1141] IR(Film,cm⁻¹) 1740, 1689

[1142] The following compounds are obtained by a method similar toReference Example 64.

[1143] [(3R)-4-Acetyl-6{3-(3-chlorobenzyloxy)phenyl}-3-isopropyl-2-oxo-1,2,3,4-tetrahydropyrazin-1-yl]aceticAcid (Reference Compound No. 64-2)

[1144] [α]_(D) ²⁰ −127.60 (c=0.95, methanol)

[1145] IR(Film,cm⁻¹)3500-3000, 1740, 1687

[1146][(3R)-4-Acetyl-6-{3-(3,5-dichlorobenzyloxy)phenyl}-3-isopropyl-2-oxo-1,2,3,4-tetrahydropyrazin-1-yl]aceticAcid (Reference Compound No. 64-3)

[1147] [α]_(D) ²⁰ −123.10 (c=0.48, methanol)

[1148] IR(Film,cm⁻¹)3500-2400, 1739, 1688, 1389

Reference Example 65{(3RS)-4-Acetyl-3-isopropyl-2-oxo-6-(3,4,5-triacetoxyphenyl)-1,2,3,4-tetrahydropyrazin-1-yl}aceticAcid (Reference Compound No. 65-1)

[1149]

[1150] Acetic anhydride is added to a suspension of {(3RS)-4-acetyl-3isopropyl-2-oxo-6-(3,4,5-trihydroxyphenyl)-1,2,3,4-tetrahydropyrazin-1-yl}aceticacid (630 mg, Reference Compound No. 62-2) in acetone (10 ml), and themixture is stirred for one week. The reaction mixture is concentratedunder reduced pressure to give the titled reference Compound (790 mg).

[1151] IR(Film,cm⁻¹)3023, 2968, 1779, 1690, 1501

[1152] The following compounds are obtained by a method similar toReference Example 65.

[1153]{(3RS)-4-Benzoyl-3-isopropyl-2-oxo-6-(3,4,5-triacetoxyphenyl)-1,2,3,4-tetrahydropyrazin-1-yl}aceticAcid (Reference Compound No. 65-2)

[1154] IR(KBr,cm⁻¹)3024, 2968, 1775, 1666, 1578, 1515, 1494, 1447

[1155]{(3RS)-4-Acetyl-6-(3,4-diacetoxyphenyl)-3-isopropyl-2-oxo-1,2,3,4-tetrahydropyrazin-1-yl}aceticAcid (Reference Compound No. 65-3)

EXAMPLES

[1156] The following Examples 1 to 21 show examples of the synthesis ofthe present synthetic intermediates [II] or the present compounds [I]described in detail in the section of “Disclosure of the Invention”.

Example 1

[1157] Isopropyl (2RS,3S)-3-{(3RS)-4-acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-hydroxy-4-phenylbutyrate(Compound No. 1-1)

[1158] N-Methylmorpholine (67 μl), 1-hydroxybenzotriazole (103 mg) andisopropyl (2RS, 3S)-3-amino-2-hydroxy-4-phenylbutyrate (144 mg,Reference Compound No. 4-1) are added to a solution of{(3RS)-4-acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}aceticacid (160 mg, Reference compound No. 51-1) in methylene chloride (5 ml).The mixture is cooled with ice,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (116 mg) isadded to the mixture, and the whole is stirred overnight. Ethyl acetateis added to the reaction mixture, the whole is washed with a 0.1 Naqueous sodium hydroxide solution, saturated brine, 0.1 N hydrochloricacid and saturated brine successively, and the organic layer is driedover anhydrous magnesium sulfate. The organic layer is concentratedunder reduced pressure, and the resulting residue is purified by silicagel column chromatography to give the titled compound (259 mg).

[1159] IR(Film,cm⁻¹)3328, 1731, 1680, 1531, 1447

[1160] The following compounds are obtained by a method similar toExample 1.

[1161] Isopropyl (2RS,3S)-3-{(3R)-4-acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-hydroxy-4-phenylbutyrate(Compound No. 1-2)

[1162] [α]_(D) ²⁰ −96.2° (c=1.0, methanol)

[1163] IR(Film,cm⁻¹)3419, 3062, 3012, 2978, 1733, 1673, 1538, 1496

[1164] Isopropyl (2RS,3S)-3-{(3S)-4-acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-hydroxy-4-phenylbutyrate(Compound No. 1-3)

[1165] [α]_(D) ²⁰ +92.7° (c=1.0, methanol)

[1166] IR(Film,cm⁻¹)3338, 3011, 2978, 1735, 1676, 1539, 1496, 1467, 1447

[1167] Isopropyl (2RS,3S)-3-{4-acetyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-hydroxy-4-phenylbutyrate(Compound No. 1-4)

[1168] IR(Film,cm⁻¹)3325, 1732, 1678

[1169] Isopropyl (2RS,3S)-3-(4-acetyl-3,3-dimethyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl)methylcarbonylamino-2-hydroxy-4-phenylbutyrate(Compound No. 1-5)

[1170] IR(Film,cm⁻¹)3338, 3062, 1732, 1679, 1655, 1531

[1171] Isopropyl (2RS,3S)-3-{(3RS)-4-acetyl-3-ethyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-hydroxy-4-phenylbutyrate(Compound No. 1-6)

[1172] IR(Film,cm⁻¹)3328, 3061, 1734, 1676, 1534, 1469, 1446

[1173] Isopropyl (2RS,3S)-3-[(3RS)-4-acetyl-3-{(1RS)-1-methylpropyl}-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl]methylcarbonylamino-2-hydroxy-4-phenylbutyrate(Compound No. 1-7)

[1174] IR(Film,cm⁻¹)3339, 1733, 1678, 1532, 1447

[1175] Isopropyl (2RS,3S)-3-{(3RS)-4-acetyl-3-isobutyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-hydroxy-4-phenylbutyrate(Compound No. 1-8)

[1176] IR(Film,cm⁻¹)3337, 3062, 1732, 1680, 1646, 1535

[1177] Isopropyl (2RS,3S)-3-{(3RS)-4-acetyl-3-cyclohexyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-hydroxy-4-phenylbutyrate(Compound No. 1-9)

[1178] IR(Film,cm⁻¹)3337, 3061, 3010, 1733, 1682, 1539, 1496, 1447

[1179] Isopropyl (2RS,3S)-3-[(3RS)-4-acetyl-3-{(1RS)-1-tert-butyldimethylsilyloxyethyl}-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl]methylcarbonylamino-2-hydroxy-4-phenylbutyrate(Compound No. 1-10)

[1180] IR(Film,cm⁻¹)3336, 3061, 1732, 1681, 1533, 1446, 1404

[1181] Isopropyl (2RS,3S)-3-{(3RS)-4-acetyl-3-methoxymethyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-hydroxy-4-phenylbutyrate(Compound No. 1-11)

[1182] IR(Film,cm⁻¹)3324, 1734, 1677, 1654, 1530, 1496, 1447

[1183] Isopropyl (2RS,3S)-3-{(3RS)-4-acetyl-3-(2-methoxyethyl)-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-hydroxy-4-phenylbutyrate(Compound No. 1-12)

[1184] IR(Film,cm⁻¹)3328, 3060, 1733, 1680, 1532

[1185] Isopropyl (2RS,3S)-3-{(3RS)-4-acetyl-3,6-diphenyl-2-oxo-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-hydroxy-4-phenylbutyrate(Compound No. 1-13)

[1186] IR(Film,cm⁻¹)3328, 3062, 1729, 1678, 1530, 1495, 1447

[1187] Isopropyl (2RS,3S)-3-{(3RS)-4-formyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-hydroxy-4-phenylbutyrate(Compound No. 1-14)

[1188] IR(Film,cm⁻¹)3338, 3061, 2975, 1733, 1683, 1537, 1448

[1189] Isopropyl (2RS,3S)-2-hydroxy-3-{(3RS)-4-isobutyryl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-4-phenylbutyrate(Compound No. 1-15)

[1190] IR(Film,cm⁻¹)3338, 1730, 1682

[1191] Isopropyl (2RS,3S)-2-hydroxy-3-{(3R)-4-isobutyryl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-4-phenylbutyrate(Compound No. 1-16)

[1192] IR(Film,cm⁻¹)3338, 1732, 1682, 1537, 1391, 1227, 1106

[1193] Isopropyl (2RS,3S)-2-hydroxy-3-{(3RS)-3-isopropyl-2-oxo-6-phenyl-4-pivaloyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-4-phenylbutyrate(Compound No. 1-17)

[1194] IR(Film,cm⁻¹)3341, 3061, 2974, 2935, 2875, 1730, 1682, 1637, 1532

[1195] Isopropyl (2RS,3S)-3-{(3RS)-4-cyclohexylcarbonyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-hydroxy-4-phenylbutyrate(Compound No. 1-18)

[1196] IR(Film,cm⁻¹)3337, 2933, 2856, 1730, 1680, 1644, 1530, 1496,1467, 1447

[1197] Isopropyl (2RS,3S)-2-hydroxy-3-{(3RS)-3-isopropyl-4-methoxycarbonyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}-methylcarbonylamino-4-phenylbutyrate(Compound No. 1-19)

[1198] Isopropyl (2RS,3S)-3-{(3RS)-4-ethoxycarbonyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-hydroxy-4-phenylbutyrate(Compound No. 1-20)

[1199] IR(Film,cm⁻¹)3348, 2978, 1714, 1687, 1529

[1200] Isopropyl (2RS,3S)-2-hydroxy-3-{(3R)-3-isopropyl-4-methoxyacetyl-2oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-4-phenylbutyrate(Compound No. 1-21)

[1201] [α]_(D) ²⁰ −88.40 (c=1.0, methanol)

[1202] IR(Film,cm⁻¹)3324, 3061, 2978, 2935, 2825, 1733, 1680, 1533, 1448

[1203] Isopropyl (2RS,3S)-3-{(3R)-4-benzoyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-hydroxy-4-phenylbutyrate(Compound No. 1-22)

[1204] [α]_(D) ²⁰ −128.1° (c=0.97, methanol)

[1205] IR(Film,cm⁻¹)3339, 3061, 2969, 1732, 1668, 1640, 1577, 1537,1494, 1447

[1206] Isopropyl (2RS,3S)-3-{(3RS)-4-(4-chlorobenzoyl)-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-hydroxy-4-phenylbutyrate(Compound No. 1-23)

[1207] IR(Film,cm⁻¹)3338, 1732, 1682, 1596

[1208] Isopropyl (2RS,3S)-2-hydroxy-3-{(3RS)-3-isopropyl-4-(4-methoxybenzoyl)-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}-methylcarbonylamino-4-phenylbutyrate(Compound No. 1-24)

[1209] Isopropyl (2RS,3S)-2-hydroxy-3-{(3RS)-3-isopropyl-4-(4-nitrobenzoyl)-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}-methylcarbonylamino-4-phenylbutyrate(Compound No. 1-25)

[1210] IR(Film,cm⁻¹)3852, 1733, 1684, 1675, 1602, 1526

[1211] Isopropyl (2RS,3S)-2-hydroxy-3-{(3RS)-3-isopropyl-2-oxo-6-phenyl-4-(3-phenylpropanoyl)-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-4-phenylbutyrate(Compound No. 1-26)

[1212] IR(Film,cm⁻¹)3319, 3027, 2967, 1732, 1687, 1530, 1496, 1447

[1213] Isopropyl (2RS,3S)-3-{(3RS)-4-benzyloxycarbonyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-hydroxy-4-phenylbutyrate(Compound No. 1-27)

[1214] IR(Film,cm⁻¹)3350, 3015, 2967, 1690, 1528

[1215] Isopropyl (2RS,3S)-2-hydroxy-3-{(3RS)-3-isopropyl-2-oxo-4-phenoxyacetyl-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-4-phenylbutyrate(Compound No. 1-28)

[1216] IR(Film,cm⁻¹)3317, 3061, 3027, 2974, 2932, 1730, 1681, 1650,1600, 1496

[1217] Isopropyl (2RS,3S)-2-hydroxy-3-{(3RS)-3-isopropyl-2-oxo-6-phenyl-4-(2-thienylcarbonyl)-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-4-phenylbutyrate(Compound No. 1-29)

[1218] IR(Film,cm⁻¹)3338, 2971, 1732, 1685, 1654, 1634, 1519

[1219] Isopropyl (2RS,3S)-2-hydroxy-3-{(3RS)-3-isopropyl-2-oxo-6-phenyl-4-(2-pyridylcarbonyl)-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-4-phenylbutyrate(Compound No. 1-30)

[1220] IR(Film,cm⁻¹)3336, 1732, 1680, 1600, 1530

[1221] Isopropyl (2RS,3S)-2-hydroxy-3-{(3RS)-3-isopropyl-2-oxo-6-phenyl-4-(3-pyridylcarbonyl)-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-4-phenylbutyrate(Compound No. 1-31)

[1222] IR(Film,cm⁻¹)3345, 2977, 1731, 1681, 1589, 1531, 1496, 1448

[1223] Isopropyl (2RS,3S)-2-hydroxy-3-{(3RS)-3-isopropyl-2-oxo-6-phenyl-4-(4-pyridylcarbonyl)-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-4-phenylbutyrate(Compound No. 1-32)

[1224] IR(Film,cm⁻¹)3341, 2977, 1730, 1680, 1645, 1599, 1549, 1495, 1447

[1225] Isopropyl (2RS,3S)-2-hydroxy-3-{(3RS)-3-isopropyl-4-methanesulfonyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}-methylcarbonylamino-4-phenylbutyrate(Compound No. 1-33)

[1226] IR(Film,cm⁻¹)3365, 3061, 3026, 2977, 2934, 2875, 11730, 1686,1602, 1529

[1227] Isopropyl (2RS,3S)-3-{(3RS)-4-benzenesulfonyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-hydroxy-4-phenylbutyrate(Compound No. 1-34)

[1228] IR(Film,cm⁻¹)3358, 3027, 2978, 2934, 1727, 1682, 1525, 1496, 1467

[1229] Isopropyl (2RS,3S)-3-{(3RS)-4-acetyl-3-isopropyl-2-oxo-6-(3,4,5-trimethoxyphenyl)-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-hydroxy-4-phenylbutyrate(Compound No. 1-35)

[1230] IR(Film,cm⁻¹)3338, 2969, 2939.2838, 1734, 1681, 1583, 1507, 1456

[1231] Isopropyl (2RS,3S)-3-{(3RS)-4-benzoyl-3-isopropyl-2-oxo-6-(3,4,5-trimethoxyphenyl)-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-hydroxy-4-phenylbutyrate(Compound No. 1-36)

[1232] IR(Film,cm⁻¹)3338, 2969, 2835, 1732, 1684, 1582, 1507, 1454

[1233] Isopropyl (2RS,3S)-2-hydroxy-3-{(3RS)-3-isopropyl-4-methoxyacetyl-2-oxo-6-(3,4,5-trimethoxyphenyl)-1,2,3,4-tetrahydropyrazin-1-yl}-methylcarbonylamino-4-phenylbutyrate(Compound No. 1-37)

[1234] IR(Film,cm⁻¹)3339, 2968, 2938, 2828, 1734, 1682, 1583, 1507, 1456

[1235] Isopropyl (2RS,3S)-3-{(3RS)-4-acetyl-6-(3,4-dimethoxyphenyl)-3-isopropyl-2-oxo-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-hydroxy-4-phenylbutyrate(Compound No. 1-38)

[1236] IR(Film,cm⁻¹)3343, 2968, 2839, 1732, 1678, 1516, 1464

[1237] Isopropyl (2RS,3S)-3-{(3RS)-4-benzoyl-6-(3,4-dimethoxyphenyl)-3-isopropyl-2-oxo-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-hydroxy-4-phenylbutyrate(Compound No. 1-39)

[1238] IR(Film,cm⁻¹)3345, 3013, 2967, 2936, 2838, 1731, 1684, 1580,1517, 1450

[1239] Isopropyl (2RS,3S)-3-{(3RS)-6-(3,4-dimethoxyphenyl)-3-isopropyl-4-methoxyacetyl-2-oxo-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-hydroxy-4-phenylbutyrate(Compound No. 1-40)

[1240] IR(Film,cm⁻¹)3416, 2967, 2936, 2838, 1732, 1678, 1583, 1517, 1466

[1241] Isopropyl (2RS,3S)-3-{(3RS)-4-benzoyl-3-isopropyl-6-(3-methoxyphenyl)-2-oxo-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-hydroxy-4-phenylbutyrate(Compound No. 1-41)

[1242] Isopropyl (2RS,3S)-3-{(3RS)-4-acetyl-3-isopropyl-2-oxo-6-(3,4,5-triacetoxyphenyl)-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-hydroxy-4-phenylbutyrate(Compound No. 1-42)

[1243] IR(Film,cm⁻¹)3339, 2981, 2936, 1781, 1738, 1680, 1564, 1530, 1500

[1244] Isopropyl (2RS,3S)-3-{(3RS)-4-benzoyl-3-isopropyl-2-oxo-6-(3,4,5-triacetoxyphenyl)-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-hydroxy-4-phenylbutyrate(Compound No. 1-43)

[1245] IR(Film,cm⁻¹)3350, 2981, 2937, 1778, 1732, 1666, 1538, 1446

[1246] Isopropyl (2RS,3S)-3-{(3RS)-4-acetyl-6-(3,4-diacetoxyphenyl)-3-isopropyl-2-oxo-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-hydroxy-4-phenylbutyrate(Compound No. 1-44)

[1247] IR(Film,cm⁻¹)3323, 2979, 1727, 1668, 1643, 1578, 1528

[1248] Isopropyl (2RS,3S)-3-{(3R)-4-acetyl-6-(3-benzyloxyphenyl)-3-isopropyl-2-oxo-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-hydroxy-4-phenylbutyrate(Compound No. 1-45)

[1249] Isopropyl (2RS,3S)-3-[(3R)-4-acetyl-6-{3-(3-chlorobenzyloxy)phenyl}-3-isopropyl-2-oxo-1,2,3,4-tetrahydropyrazin-1-yl]methylcarbonylamino-2-hydroxy-4-phenylbutyrate(Compound No. 1-46)

[1250] IR(Film,cm⁻¹)3838, 1732, 1677, 1388

[1251] Isopropyl (2RS,3S)-3-[(3R)-4-acetyl-6-{3-(3,5-dichlorobenzyloxy)phenyl}-3-isopropyl-2-oxo-1,2,3,4-tetrahydropyrazin-1-yl]methylcarbonylamino-2-hydroxy-4-phenylbutyrate(Compound No. 1-47)

[1252] IR(Film,cm⁻¹)3338, 1733, 1680, 1432, 1388, 1280, 1213

[1253] Methyl(2S)-2-{(3RS)-4-acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-3-phenylpropionate(Compound No. 1-48)

[1254] IR(Film,cm⁻¹)3316, 3062, 3012, 2964, 1745, 1682, 1650, 1532,1446, 1388

[1255](2S)-2-{(3R)-4-Isobutyryl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-1,3-diphenylpropanone(Compound No. 1-49)

[1256]N¹-Methoxy-(2S)-2-{(3RS)-4-acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-3-phenylpropionamide(Compound No. 1-50)

[1257] IR(Film,cm⁻¹)3280, 1671N¹-Methoxy-N¹-methyl-(2S)-2-{(3RS)-4-acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-3-phenylpropionamide(Compound No. 1-51)

[1258] IR(Film,cm⁻¹)3212, 1674, 1388

[1259](2S)-2-{(3RS)-3-Isopropyl-2-oxo-4-methoxyacetyl-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-1-morpholino-1-oxo-3phenylpropane (Compound No. 1-52)

[1260] IR(Film,cm⁻¹)3306, 3060, 3006, 2965, 2929, 2861, 1682, 1644, 1538

[1261](2S)-2-{(3RS)-3-Isopropyl-2-oxo-4-methoxyacetyl-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-1-oxo-3-phenyl-1-piperidinopropane(Compound No. 1-53)

[1262] IR(Film,cm⁻¹)3294, 3004, 2936, 2857, 1684, 1628, 1540, 1496,1447, 1388

[1263] (2S)-1-{(2S)-2-Carbamoylpyrrolidin-1-yl}-2-{(3RS)-3-isopropyl-4methoxyacetyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}-methylcarbonylamino-1-oxo-3-phenylpropane(Compound No. 1-54)

[1264] IR(Film,cm⁻¹)3306, 1682, 1630, 1447, 754

[1265](2S)-1-(4-tert-Butoxycarbonylpiperazin-1-yl)-2-{(3RS)-3-isopropyl-4-methoxyacetyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}-methylcarbonylamino-1-oxo-3-phenylpropane(Compound No. 1-55)

[1266] IR(Film,cm⁻¹)3306, 3007, 2973, 2931, 1682, 1644, 1447, 1416, 1367

Example 2

[1267] Isopropyl(3S)-3-{(3RS)-4-acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-oxo-4-phenylbutyrate(Compound No. 2-1)

[1268] Acetic anhydride (2.0 ml) is added to a solution of isopropyl(2RS,3S)-3-{(3RS)-4-acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-hydroxy-4-phenylbutyrate(220 mg, Compound No. 1-1) in dimethyl sulfoxide (2.0 ml), and themixture is stirred overnight. Water is added to the reaction mixture,and the whole is stirred for 1.5 hours. Water and sodiumhydrogencarbonate is added to the reaction mixture to basify the system,and the whole is extracted with ethyl acetate. The extract is washedwith saturated brine and dried over anhydrous magnesium sulfate. Theextract is concentrated under reduced pressure, and the resultingresidue is purified by silica gel column chromatography to give thetitled compound (188 mg).

[1269] IR(Film,cm⁻¹)3306, 1725, 1677, 1525, 1446

[1270] The following compounds are obtained by a method similar toExample 2.

[1271] Isopropyl(3S)-3-{(3R)-4-acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-oxo-4-phenylbutyrate(Compound No. 2-2)

[1272] [α]_(D) ²⁰ −86.7° (c=1.0, methanol)

[1273] IR(Film,cm⁻¹)3306, 2978, 2935, 1725, 1679, 1529, 1446

[1274] Isopropyl(3S)-3-{(3S)-4-acetyl-3-isopropyl-2′-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-oxo-4-phenylbutyrate(Compound No. 2-3)

[1275] [α]_(D) ²⁰ +86.50 (c=0.99, methanol)

[1276] IR(Film,cm⁻¹)3306, 2978, 2935, 1725, 1679, 1529, 1446

[1277] Isopropyl(3S)-3-{4-acetyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-oxo-4-phenylbutyrate(Compound No. 2-4)

[1278] IR(Film,cm⁻¹)3854, 1725, 1679, 1536

[1279] Isopropyl(3S)-3-(4-acetyl-3,3-dimethyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl)methylcarbonylamino-2-oxo-4-phenylbutyrate(Compound No. 2-5)

[1280] IR(Film,cm⁻¹)3302, 1731, 1670, 1539

[1281] Isopropyl(3S)-3-{(3RS)-4-acetyl-3-ethyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-oxo-4-phenylbutyrate(Compound No. 2-6)

[1282] IR(Film,cm⁻¹)3306, 11726, 1680, 1649, 1530, 1446

[1283] Isopropyl(3S)-3-[(3RS)-4-acetyl-3-{(1RS)-1-methylpropyl}-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl]methylcarbonylamino-2-oxo-4-phenylbutyrate(Compound No. 2-7)

[1284] IR(Film,cm⁻¹)3305, 1726, 1682, 1540, 1497, 1447

[1285] Isopropyl(3S)-3-{(3RS)-4-acetyl-3-isobutyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-oxo-4-phenylbutyrate(Compound No. 2-8)

[1286] IR(Film,cm⁻¹)3306, 1743, 1727, 1681, 1646, 1528

[1287] Isopropyl (3S)-3-{(3RS)-4-acetyl-3-cyclohexyl2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-oxo-4-phenylbutyrate(Compound No. 2-9)

[1288] IR(Film,cm⁻¹)3315, 3061, 1727.1679, 1530, 1448

[1289] Isopropyl(3S)-3-[(3RS)-4-acetyl-3-{(1RS)-1-tert-butyldimethylsilyloxyethyl}-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl]-methylcarbonylamino-2-oxo-4-phenylbutyrate(Compound No. 2-10)

[1290] IR(Film,cm⁻¹)3305, 11725, 1686, 1524, 1472, 1446, 1404

[1291] Isopropyl(3S)-3-{(3RS)-4-acetyl-3-methoxymethyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-oxo-4-phenylbutyrate(Compound No. 2-11)

[1292] IR(Film,cm⁻¹)3296, 2830, 11723, 1682, 1651, 1520, 1496, 1446

[1293] Isopropyl(3S)-3-{(3RS)-4-acetyl-3-(2-methoxyethyl)-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-oxo-4-phenylbutyrate(Compound No. 2-12)

[1294] IR(Film,cm⁻¹)3308, 1727, 1680, 1538, 1448

[1295] Isopropyl(3S)-3-{(3RS)-4-acetyl-3,6-diphenyl-2-oxo-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-oxo-4-phenylbutyrate(Compound No. 2-13)

[1296] IR(Film,cm⁻¹)3308, 3061, 3028, 1725, 1678, 1526, 1496, 1448

[1297] Isopropyl(3S)-3-{(3RS)-4-formyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-oxo-4-phenylbutyrate(Compound No. 2-14)

[1298] IR(Film,cm⁻¹)3308, 2975, 1727, 1682, 1654, 1538, 1452

[1299] Isopropyl(3S)-3-{(3RS)-4-isobutyryl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-oxo-4-phenylbutyrate(Compound No. 2-15)

[1300] IR(Film,cm⁻¹)3316, 1725, 1679, 1529

[1301] Isopropyl(3S)-3-{(3R)-4-isobutyryl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-oxo-4-phenylbutyrate(Compound No. 2-16)

[1302] IR(Film,cm⁻¹)3324, 1727, 1682, 1524, 1390, 1227

[1303] Isopropyl(3S)-3-{(3RS)-3-isopropyl-2-oxo-6-phenyl-4-pivaloyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-oxo-4-phenylbutyrate(Compound No. 2-17)

[1304] IR(Film,cm⁻¹)3306, 2974, 2874, 1725, 1690, 1666, 1641

[1305] Isopropyl(3S)-3-{(3RS)-4-cyclohexylcarbonyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-oxo-4-phenylbutyrate(Compound No. 2-18)

[1306] IR(Film,cm⁻¹)3316, 2933, 2857, 1726, 1678, 1643, 1527, 1449

[1307] Isopropyl(3S)-3-{(3RS)-3-isopropyl-4-methoxycarbonyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-oxo-4-phenylbutyrate(Compound No. 2-19)

[1308] IR(Film,cm⁻¹)3334, 2965, 1720, 1689, 1528, 1446

[1309] Isopropyl(3S)-3-{(3RS)-4-ethoxycarbonyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-oxo-4-phenylbutyrate(Compound No. 2-20)

[1310] IR(Film,cm⁻¹)3329, 2979, 1716, 1687, 1522

[1311] Isopropyl(3S)-3-{(3R)-3-isopropyl-4-methoxyacetyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-oxo-4-phenylbutyrate(Compound No. 2-21)

[1312] [α]_(D) ²⁰ −80.2° (c=0.53, methanol)

[1313] IR(Film,cm⁻¹)3306, 2966, 2934, 1725, 1683, 1522

[1314] Isopropyl(3S)-3-{(3R)-4-benzoyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-oxo-4-phenylbutyrate(Compound No. 2-22)

[1315] [α]_(D) ²⁰ −113.6° (c=1.0, methanol)

[1316] IR(Film,cm⁻¹)3314, 3061, 3027, 1725, 1689, 1578, 1528, 1495, 1447

[1317] Isopropyl(3S)-3-{(3RS)-4-(4-chlorobenzoyl)-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2oxo-4-phenylbutyrate (Compound No. 2-23)

[1318] IR(Film,cm⁻¹)3789, 1725, 1689, 1642

[1319] Isopropyl(3S)-3-{(3RS)-3-isopropyl-4-(4-methoxybenzoyl)-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-oxo-4-phenylbutyrate(Compound No. 2-24)

[1320] IR(Film,cm⁻¹)3306, 1725, 1689, 1633, 1512

[1321] Isopropyl(3S)-3-{(3RS)-3-isopropyl-4-(4-nitrobenzoyl)-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-oxo-4-phenylbutyrate(Compound No. 2-25)

[1322] IR(Film,cm⁻¹)3318, 1740, 1681, 1650, 1601, 1526

[1323] Isopropyl(3S)-3-{(3RS)-3-isopropyl-2-oxo-6-phenyl-4-(3-phenylpropanoyl)-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-oxo-4-phenylbutyrate(Compound No. 2-26)

[1324] IR(Film,cm⁻¹)3310, 3061, 3027, 2966, 11725, 1678, 1647, 1527,1497

[1325] Isopropyl(3S)-3-{(3RS)-4-benzyloxycarbonyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-oxo-4-phenylbutyrate(Compound No. 2-27)

[1326] IR(Film,cm⁻¹)3332, 3028, 2966, 1745, 1714, 1688, 1519

[1327] Isopropyl(3S)-3-{(3RS)-3-isopropyl-2-oxo-4-phenoxyacetyl-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-oxo-4-phenylbutyrate(Compound No. 2-28)

[1328] IR(Film,cm⁻¹)3319, 3062, 3027, 2978, 2935, 2874, 1726, 1681, 1601

[1329] Isopropyl(3S)-3-{(3RS)-3-isopropyl-2-oxo-6-phenyl-4-(2-thienylcarbonyl)-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-oxo-4-phenylbutyrate(Compound No. 2-29)

[1330] IR(Film,cm⁻¹)3326, 2975, 2935, 1744, 1688, 1630, 1517

[1331] Isopropyl(3S)-3-{(3RS)-3-isopropyl-2-oxo-6-phenyl-4-(2-pyridylcarbonyl)-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-oxo-4-phenylbutyrate(Compound No. 2-30)

[1332] IR(Film,cm⁻¹)3314, 1725, 1683.1600, 1521

[1333] Isopropyl(3S)-3-{(3RS)-3-isopropyl-2-oxo-6-phenyl-4-(3-pyridylcarbonyl)-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-oxo-4-phenylbutyrate(Compound No. 2-31)

[1334] IR(Film,cm⁻¹)3319, 2973, 1726, 1674, 1589, 1529, 1447

[1335] Isopropyl(3S)-3-{(3RS)-3-isopropyl-2-oxo-6-phenyl-4-(4-pyridylcarbonyl)-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-oxo-4-phenylbutyrate(Compound No. 2-32)

[1336] IR(Film,cm⁻¹)3306, 2978, 1724, 1687, 1647, 1599, 1550, 1526,1495, 1447

[1337] Isopropyl(3S)-3-{(3RS)-3-isopropyl-4-methanesulfonyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-yl}methylcarbonylamino-2-oxo-4-phenylbutyrate(Compound No. 2-33)

[1338] IR(Film,cm⁻¹)3358, 3027, 2978, 2934, 1727, 1682, 1525, 1496, 1467

[1339] Isopropyl(3S)-3-{(3RS)-4-benzenesulfonyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-oxo-4-phenylbutyrate(Compound No. 2-34)

[1340] IR(Film,cm⁻¹)3368, 1726, 1686, 1447

[1341] Isopropyl(3S)-3-{(3RS)-4-acetyl-3-isopropyl-2-oxo-6-(3,4,5-trimethoxyphenyl)-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-oxo-4-phenylbutyrate(Compound No. 2-35)

[1342] IR(Film,cm⁻¹)3311, 2969, 2839, 1727, 1679, 1583, 1507, 1456

[1343] Isopropyl(3S)-3-{(3RS)-4-benzoyl-3-isopropyl-2-oxo-6-(3,4,5-trimethoxyphenyl)-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonyl-amino-2-oxo-4-phenylbutyrate(Compound No. 2-36)

[1344] IR(Film,cm⁻¹)3323, 2968, 2938, 2837, 1727, 1670, 1582, 1507, 1454

[1345] Isopropyl(3S)-3-{(3RS)-3-isopropyl-4-methoxyacetyl-2-oxo-6-(3,4,5-trimethoxyphenyl)-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-oxo-4-phenylbutyrate(Compound No. 2-37)

[1346] IR(Film,cm⁻¹)3311, 2968, 2938.2830, 1726, 1681, 1583, 1508, 1456

[1347] Isopropyl(3S)-3-{(3RS)-4-acetyl-6-(3,4-dimethoxyphenyl)-3-isopropyl-2-oxo-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-oxo-4-phenylbutyrate(Compound No. 2-38)

[1348] IR(Film,cm⁻¹)3323, 3017, 2968, 2937, 2839, 1726, 1678, 1603,1583, 1516,

[1349] Isopropyl(3S)-3-{(3RS)-4-benzoyl-6-(3,4-dimethoxyphenyl)-3-isopropyl-2-oxo-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-oxo-4-phenylbutyrate(Compound No. 2-39)

[1350] IR(Film,cm⁻¹)3338, 2967, 2839, 11726, 1681, 1603, 1580, 1517,1449

[1351] Isopropyl(3S)-3-{(3RS)-6-(3,4-dimethoxyphenyl)-3-isopropyl-4-methoxyacetyl-2-oxo-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-oxo-4-phenylbutyrate(Compound No. 2-40)

[1352] IR(Film,cm⁻¹)3322, 2967, 2936, 2838, 1727, 1680, 1603, 1583,1517, 1465

[1353] Isopropyl(3S)-3-{(3RS)-4-benzoyl-3-isopropyl-6-(3-methoxyphenyl)-2-oxo-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-oxo-4-phenylbutyrate(Compound No. 2-41)

[1354] Isopropyl(3S)-3-{(3RS)-4-acetyl-3-isopropyl-2-oxo-6-(3,4,5-triacetoxyphenyl)-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-oxo-4-phenylbutyrate(Compound No. 2-42)

[1355] IR(Film,cm⁻¹)3338, 2986, 2937, 1781, 1745, 1682, 1651, 1498, 1455

[1356] Isopropyl(3S)-3-{(3RS)-4-benzoyl-3-isopropyl-2-oxo-6-(3,4,5-triacetoxyphenyl)-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-oxo-4-phenylbutyrate(Compound No. 2-43)

[1357] IR(Film,cm⁻¹)3308, 2981, 2936, 1781, 1726, 1670, 1522, 1498

[1358] Isopropyl(3S)-3-{(3RS)-4-acetyl-6-(3,4-diacetoxyphenyl)-3-isopropyl-2-oxo-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-oxo-4-phenylbutyrate(Compound No. 2-44)

[1359] IR(Film,cm⁻¹)3307, 3021, 2981, 2936, 1770, 1725, 1682, 1650,1576, 1505

[1360](2S)-2-{(3RS)-4-Acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-1-oxo-3-phenyl-1-(1,3-thiazol-2-yl)propane(Compound No. 2-45)

[1361](2S)-2-{(3RS)-4-Acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-1-(1,3-benzothiazol-2-yl)-1-oxo-3-phenylpropane(Compound No. 2-46)

[1362](2S)-2-{(3RS)-4-Acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-1-(4,5-dihydro-1,3-oxazol-2-yl)-1-oxo-3-phenylpropane(Compound No. 2-47)

[1363] IR(Film,cm⁻¹)3307, 2965, 1750, 1678, 1542, 1496, 1446

[1364](2S)-2-{(3RS)-4-Acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-1-(4,5-dihydro-1,3-thiazol-2-yl)-1-oxo-3-phenylpropane(Compound No. 2-48)

[1365] IR(Film,cm⁻¹)3308, 3012, 2965, 1751, 1680, 1529, 1445

[1366](2S)-1-(4,5-Dihydro-1,3-oxazol-2-yl)-2-{(3RS)-3-isopropyl-4-methoxyacetyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}-methylcarbonylamino-1-oxo-3-phenylpropane(Compound No. 2-49)

[1367] IR(KBr,cm⁻¹)3306, 2964, 1746, 1681, 1530, 1447

[1368] (2S)-1-(1-Aza-3-oxaspiro[4,4]non-1-en-2-yl)-2-{(3RS)-4-benzoyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-1-oxo-3-phenylpropane(Compound No. 2-50)

[1369] IR(Film,cm⁻¹)3308, 2964, 2873, 1731, 1670, 1519, 1447

[1370](2S)-1-(1-Aza-3-oxaspiro[4,4]non-1-en-2-yl)-2-{(3RS)-3-isopropyl-4-methoxyacetyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}-methylcarbonylamino-1-oxo-3-phenylpropane(Compound No. 2-51)

[1371] IR(Film,cm⁻¹)3310, 2963, 1729, 1681, 1521, 1448

[1372](2S)-1-(4,4-Dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-2-{(3RS)-3-isopropyl-4-methoxyacetyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}-methylcarbonylamino-1-oxo-3-phenylpropane(Compound No. 2-52)

[1373] IR(Film,cm⁻¹)3305, 3064, 2971, 1733, 1663, 1588, 1570, 1440

[1374](2S)-2-{(3RS)-4-Benzenesulfonyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-1-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-1-oxo-3-phenylpropane(Compound No. 2-53)

[1375] IR(Film,cm⁻¹)3348, 3063, 3027, 2968, 2932, 1734, 1682, 1531, 1447

[1376](2S)-1-(4,4-Dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-2-{(3RS)-3-isopropyl-2-oxo-6-phenyl-4-pivaloyl-1,2,3,4-tetrahydropyrazin-1-yl}-methylcarbonylamino-1-oxo-3-phenylpropane(Compound No. 2-54)

[1377] IR(Film,cm⁻¹)3319, 2970, 1731, 1679, 1518, 1448

[1378](2S)-2-{(3RS)-4-Acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-1-(5,5-dimethyl-4,5-dihydro-1,3-thiazol-2-yl)-1-oxo-3-phenylpropane(Compound No. 2-55)

[1379] IR(Film,cm⁻¹)3308, 3013, 2964, 2930, 1682, 1581, 1520, 1446

[1380](2S)-1-(5,5-Dimethyl-4,5-dihydro-1,3-thiazol-2-yl)-2-{(3R)-3-isopropyl-2-oxo-6-phenyl-4-(2-pyridylcarbonyl)-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-1-oxo-3-phenylpropane(Compound No. 2-56)

[1381] IR(Film,cm⁻¹)33117, 3060, 3024, 2963, 2928, 1682, 1644, 1584,1568, 1520, 1468

[1382](2S)-1-(5,5-Dimethyl-4,5-dihydro-1,3-thiazol-2-yl)-2-{(3RS)-3-isopropyl-2-oxo-6-phenyl-4-(3-pyridylcarbonyl)-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-1-oxo-3-phenylpropane(Compound No. 2-57)

[1383] IR(Film,cm⁻¹)3325, 3015, 2931, 1682, 1644, 1588, 1520, 1446

[1384] Isopropyl(3S)-3-{(3R)-4-acetyl-6-(3-benzyloxyphenyl)-3-isopropyl-2-oxo-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-oxo-4-phenylbutyrate(Compound No. 2-58)

[1385] IR(Film,cm⁻¹)3306, 1725, 1680.1599

[1386] Isopropyl(3S)-3-[(3R)-4-acetyl-6-{3-(3-chlorobenzyloxy)phenyl}-3-isopropyl-2-oxo-1,2,3,4-tetrahydropyrazin-1-yl]methylcarbonylamino-2-oxo-4-phenylbutyrate(Compound No. 2-59)

[1387] IR(Film,cm⁻¹)3299, 1725, 1679, 1599

[1388] Isopropyl(3S)-3-[(3R)-4-acetyl-6-{3-(3,5-dichlorobenzyloxy)-phenyl}-3-isopropyl-2-oxo-1,2,3,4-tetrahydropyrazin-1-yl]methylcarbonylamino-2-oxo-4-phenylbutyrate(Compound No. 2-60)

[1389] [α]_(D) ²⁰ −65.7° (c=0.51, methanol)

[1390] IR(Film,cm⁻¹)3304, 1725, 1679, 1571, 1432, 1387

[1391] Isopropyl(3S)-3-{(2RS)-2-isopropyl-3-oxo-3,4-dihydro-2H-1,4-thiazin-4-yl}methylcarbonylamino-2-oxo-4-phenylbutyrate(Compound No. 2-61)

[1392] IR(Film,cm⁻¹)3305, 1727, 1665, 1529, 1271

[1393] Isopropyl(3S)-3-{(2RS)-5-ethyl-2-isopropyl-3-oxo-3,4-dihydro-2H-1,4-thiazin-4-yl}methylcarbonylamino-2-oxo-4-phenylbutyrate(Compound No. 2-62)

[1394] IR(Film,cm⁻¹)3324, 3062, 1726, 1667, 1524, 1497, 1455, 1375, 1258

[1395] Isopropyl(3S)-3-{(2RS)-2-isopropyl-3-oxo-5-phenyl-3,4-dihydro-2H-1,4-thiazin-4-yl}methylcarbonylamino-2-oxo-4-phenylbutyrate(Compound No. 2-63)

[1396] IR(Film,cm⁻¹)3305, 1727, 1665, 1529, 1271

[1397] Isopropyl(3S)-3-{(2RS)-5-(4-fluorophenyl)-2-isopropyl-3-oxo-3,4-dihydro-2H-1,4-thiazin-4-yl}methylcarbonylamino-2-oxo-4-phenylbutyrate(Compound No. 2-64)

[1398] IR(Film,cm⁻¹)3326, 1726, 1673, 1508, 1227

[1399] Isopropyl(3S)-3-{(2RS)-2-isopropyl-5-(4-methoxyphenyl)-3-oxo-3,4-dihydro-2H-1,4-thiazin-4-yl}methylcarbonylamino-2-oxo-4-phenylbutyrate(Compound No. 2-65)

[1400] IR(Film,cm⁻¹)3326, 1725, 1670, 1511, 1249

[1401] Isopropyl(3S)-3-{(2RS)-2-methyl-3-oxo-3,4-dihydro-2H-1,4-thiazin-4-yl}methylcarbonylamino-2-oxo-4-phenylbutyrate(Compound No. 2-66)

[1402] IR(Film,cm⁻¹)3304, 1726, 1673, 1538

[1403] Isopropyl(3S)-3-{(2RS)-2-ethyl-3-oxo-3,4-dihydro-2H-1,4-thiazin-4-yl}methylcarbonylamino-2-oxo-4-phenylbutyrate(Compound No. 2-67)

[1404] IR(Film,cm⁻¹)3307, 3064, 3027, 1725, 1667, 1527, 1496, 1454

[1405] Isopropyl(3S)-3-{(2RS)-3-oxo-2-propyl-3,4-dihydro-2H-1,4-thiazin-4-yl}methylcarbonylamino-2-oxo-4-phenylbutyrate(Compound No. 2-68)

[1406] Isopropyl(3S)-3-{(2RS)-2-methoxy-3-oxo-3,4-dihydro-2H-1,4-thiazin-4-yl}methylcarbonylamino-2-oxo-4-phenylbutyrate(Compound No. 2-69)

[1407] Isopropyl(3S)-3-[(1RS)-1-{(2RS)-2-isopropyl-3-oxo-3,4-dihydro-2H-1,4-thiazin-4-yl}ethyl]carbonylamino-2-oxo-4-phenylbutyrate(Compound No. 2-70)

[1408] Isopropyl(3S)-3-[(1RS)-1-{(2RS)-2-isopropyl-3-oxo-3,4-dihydro-2H-1,4-thiazin-4-yl}propyl]carbonylamino-2-oxo-4-phenylbutyrate(Compound No. 2-71)

[1409] Isopropyl(3S)-3-[1-{(2RS)-2-isopropyl-3-oxo-3,4-dihydro-2H-1,4-thiazin-4-yl}-2-phenylethyl]carbonylamino-2-oxo-4-phenylbutyrate(Compound No. 2-72)

[1410](3S)-3-{(3RS)-4-Acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}carbonylamino-2-oxo-4-phenylbutyramide(Compound No. 2-73)

[1411]N¹-Isopropyl-(3RS)-3-{(3RS)-4-acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-oxo-4-phenylbutyramide(Compound No. 2-74)

[1412] IR(Film,cm⁻¹)3305, 2970, 2933, 1671, 1522

[1413]N¹,N¹-Dimethyl-(3RS)-3-{(3RS)-4-acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-oxo-4-phenylbutyramide(Compound No. 2-75)

[1414] IR(Film,cm⁻¹)3305, 3061, 3029, 2964, 2934, 1722, 1682, 1640, 1540

Example 3

[1415] The following compound is obtained by a method similar to Example1.

[1416] (2RS,3RS)-3-{(3RS)-4-Acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-hydroxy-4-phenyl-1,1,1-trifluorobutane(Compound No. 3-1)

[1417] The following compounds are obtained by a method similar toExample 3.

[1418] IR(Film,cm⁻¹)3307, 3064, 3028, 1669, 1646, 1546

[1419] (2RS, 3RS)-3-{(3R)-4-Acetyl-3-isopropyl-2-oxo-6-phenyl1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-hydroxy-4-phenyl-1,1,1-trifluorobutane(Compound No. 3-2)

[1420] (2RS,3RS)-3-{(3S)-4-Acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-hydroxy-4-phenyl-1,1,1-trifluorobutane(Compound No. 3-3)

[1421] (2RS,3RS)-3-(4-Acetyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl)methylcarbonylamino-2-hydroxy-4-phenyl-1,1,1-trifluorobutane(Compound No. 3-4)

[1422] IR(Film,cm⁻¹)3322, 3064, 3026, 1675, 1548, 1497, 1446

[1423] (2RS,3RS)-3-(4-Acetyl-3,3-dimethyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl)methylcarbonylamino-2-hydroxy-4-phenyl-1,1,1-trifluorobutane(Compound No. 3-5)

[1424] IR(Film,cm⁻¹)3322, 3064, 3026, 1675, 1548, 1497, 1446

[1425] (2RS,3RS)-3-{(3RS)-4-Acetyl-3-ethyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-hydroxy-4-phenyl-1,1,1-trifluorobutane(Compound No. 3-6)

[1426] IR(Film,cm⁻¹)3308, 3064, 3027, 1669, 1646, 1540, 1498, 1447

[1427] (2RS,3RS)-3-[(3RS)-4-Acetyl-3-{(1RS)-1-methylpropyl}-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl]methylcarbonylamino-2-hydroxy-4-phenyl-1,1,1-trifluorobutane(Compound No. 3-7)

[1428] IR(Film,cm⁻¹)3314, 3064, 3028, 1670, 1541, 1497, 1447

[1429] (2RS,3RS)-3-{(3RS)-4-Acetyl-3-isobutyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-hydroxy-4-phenyl-1,1,1-trifluorobutane(Compound No. 3-8)

[1430] IR(Film,cm⁻¹)3315, 3016, 1671, 1646, 1548

[1431] (2RS,3RS)-3-{(3RS)-4-Acetyl-3-cyclohexyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-hydroxy-4-phenyl-1,1,1-trifluorobutane(Compound No. 3-9)

[1432] IR(Film,cm⁻¹)3312, 3064, 3026, 1670, 1541, 1448

[1433] (2RS,3RS)-3-[(3RS)-4-Acetyl-3-{(1RS)-1-tert-butyldimethylsilyloxyethyl}-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl]methylcarbonylamino-2-hydroxy-4-phenyl-1,1,1-trifluorobutane(Compound No. 3-10)

[1434] (2RS,3RS)-3-{(3RS)-4-Acetyl-3-methoxymethyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-hydroxy-4-phenyl-1,1,1-trifluorobutane(Compound No. 3-11)

[1435] (2RS,3RS)-3-{(3RS)-4-Acetyl-3-(2-methoxyethyl)-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-hydroxy-4-phenyl-1,1,1-trifluorobutane(Compound No. 3-12)

[1436] IR(Film,cm⁻¹)3307, 3064, 3026, 1672, 1649, 1540, 1447

[1437] (2RS,3RS)-3-{(3RS)-4-Acetyl-3,6-diphenyl-2-oxo-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-hydroxy-4-phenyl-1,1,1-trifluorobutane(Compound No. 3-13)

[1438] IR(Film,cm⁻¹)3316, 3064, 3027, 1668, 1549, 1496, 1448

[1439] (2RS,3RS)-3-{(3RS)-4-Formyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-hydroxy-4-phenyl-1,1,1-trifluorobutane(Compound No. 3-14)

[1440] IR(Film,cm⁻¹)3307, 3064, 3027, 2966, 1676, 1654, 1540, 1496, 1447

[1441] (2RS,3RS)-2-Hydroxy-3-{(3RS)-4-isobutyryl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-4-phenyl-1,1,1-trifluorobutane(Compound No. 3-15)

[1442] IR(Film,cm⁻¹)3323, 1665, 1547

[1443] (2RS,3RS)-2-Hydroxy-3-{(3R)-4-isobutyryl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-4-phenyl-1,1,1-trifluorobutane(Compound No. 3-16)

[1444] IR(Film,cm⁻¹)3328, 1666, 1546

[1445] (2RS,3RS)-2-Hydroxy-3-{(3RS)-3-isopropyl-2-oxo-6-phenyl-4-pivaloyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-4-phenyl-1,1,1-trifluorobutane(Compound No. 3-17)

[1446] IR(Film,cm⁻¹)3789, 1660, 1547

[1447] (2RS,3RS)-3-{(3RS)-4-Cyclohexylcarbonyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-hydroxy-4-phenyl-1,1,1-trifluorobutane(Compound No. 3-18)

[1448] IR(Film,cm⁻¹)3324, 3064, 3015, 2934, 2857, 1666, 1548, 1497, 1447

[1449] (2RS,3RS)-2-Hydroxy-3-{(3RS)-3-isopropyl-4-methoxycarbonyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-4-phenyl-1,1,1-trifluorobutane(Compound No. 3-19)

[1450] IR(Film,cm⁻¹)3326, 2964, 1688, 1536, 1446

[1451] (2RS,3RS)-3-{(3RS)-4-Ethoxycarbonyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-hydroxy-4-phenyl-1,1,1-trifluorobutane(Compound No. 3-20)

[1452] IR(Film,cm⁻¹)3327, 3026, 2967, 1688

[1453] (2RS,3RS)-2-Hydroxy-3-{(3R)-3-isopropyl-4-methoxyacetyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-4-phenyl-1,1,1-trifluorobutane(Compound No. 3-21)

[1454] IR(Film,cm⁻¹)3321, 1678

[1455] (2RS,3RS)-3-{(3R)-4-Benzoyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-hydroxy-4-phenyl-1,1,1-trifluorobutane(Compound No. 3-22)

[1456] IR(Film,cm⁻¹)3316, 1666

[1457] (2RS,3RS)-3-{(3RS)-4-(4-Chlorobenzoyl)-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-hydroxy-4-phenyl-1,1,1-trifluorobutane(Compound No. 3-23)

[1458] IR(Film,cm⁻¹)3786, 1664, 1548

[1459] (2RS,3RS)-2-Hydroxy-3-{(3RS)-3-isopropyl-4-(4-methoxybenzoyl)-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-4-phenyl-1,1,1-trifluorobutane(Compound No. 3-24)

[1460] IR(Film,cm⁻¹)3319, 1666, 1660

[1461] (2RS,3RS)-2-Hydroxy-3-{(3RS)-3-isopropyl-4-(4-nitrobenzoyl)-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-4-phenyl-1,1,1-trifluorobutane(Compound No. 3-25)

[1462] (2RS,3RS)-2-Hydroxy-3-{(3RS)-3-isopropyl-2-oxo-6-phenyl-4-(3-phenylpropanoyl)-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-4-phenyl-1,1,1-trifluorobutane(Compound No. 3-26)

[1463] (2RS,3RS)-3-{(3RS)-4-Benzyloxycarbonyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-hydroxy-4-phenyl-1,1,1-trifluorobutane(Compound No. 3-27)

[1464] IR(Film,cm⁻¹)3330, 3064, 3028, 2966, 1688, 1549

[1465] (2RS,3RS)-2-Hydroxy-3-{(3RS)-3-isopropyl-2-oxo-4-phenoxyacetyl-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-4-phenyl-1,1,1-trifluorobutane(Compound No. 3-28)

[1466] IR(Film,cm⁻¹)3324, 1762, 1682, 1496

[1467] (2RS,3RS)-2-Hydroxy-3-{(3RS)-3-isopropyl-2-oxo-6-phenyl-4-(2-thienylcarbonyl)-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-4-phenyl-1,1,1-trifluorobutane(Compound No. 3-29)

[1468] IR(Film,cm⁻¹)3323, 2966, 1676, 1628, 1544

[1469] (2RS,3RS)-2-Hydroxy-3-{(3RS)-3-isopropyl-2-oxo-6-phenyl-4-(2-pyridylcarbonyl)-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-4-phenyl-1,1,1-trifluorobutane(Compound No. 3-30)

[1470] IR(Film,cm⁻¹)3321, 1665, 1541, 1442

[1471] (2RS,3RS)-2-Hydroxy-3-{(3RS)-3-isopropyl-2-oxo-6-phenyl-4-(3-pyridylcarbonyl)-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-4-phenyl-1,1,1-trifluorobutane(Compound No. 3-31)

[1472] IR(Film,cm⁻¹)3322, 3028, 2967, 1670, 1638, 1590, 1549, 1447

[1473] (2RS,3RS)-2-Hydroxy-3-{(3RS)-3-isopropyl-2-oxo-6-phenyl-4-(4-pyridylcarbonyl)-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-4-phenyl-1,1,1-trifluorobutane(Compound No. 3-32)

[1474] IR(Film,cm⁻¹)3325, 3027, 2967, 1674, 1642, 1601, 1551, 1496, 1447

[1475] (2RS,3RS)-2-Hydroxy-3-{(3RS)-3-isopropyl-4-methanesulfonyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-4-phenyl-1,1,1-trifluorobutane(Compound No. 3-33)

[1476] (2RS,3RS)-3-{(3RS)-4-Benzenesulfonyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-hydroxy-4-phenyl-1,1,1-trifluorobutane(Compound No. 3-34)

[1477] IR(Film,cm⁻¹)3369, 1675, 1538

[1478] (2RS,3RS)-3-{(3RS)-4-Acetyl-3-isopropyl-2-oxo-6-(3,4,5-trimethoxyphenyl)-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-hydroxy-4-phenyl-1,1,1-trifluorobutane(Compound No. 3-35)

[1479] IR(Film,cm⁻¹)3314, 3086, 3012, 2968, 2877, 2835, 1671, 1583,1547, 1507,

[1480] (2RS,3RS)-3-{(3RS)-4-Benzoyl-3-isopropyl-2-oxo-6-(3,4,5-trimethoxyphenyl)-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-hydroxy-4-phenyl-1,1,1-trifluorobutane(Compound No. 3-36)

[1481] IR(Film,cm⁻¹)3324, 3065, 3012.2966, 2837, 1665, 1583, 1546, 1509,1453

[1482] (2RS,3RS)-2-Hydroxy-3-{(3RS)-3-isopropyl-4-methoxyacetyl-2-oxo-6-(3,4,5-trimethoxyphenyl)-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-4-phenyl-1,1,1-trifluorobutane(Compound No. 3-37)

[1483] IR(Film,cm⁻¹)3324, 3066, 3010, 2966, 2940, 2830, 1682, 1584,1540, 1507,

[1484] (2RS,3RS)-3-{(3RS)-4-Acetyl-6-(3,4-dimethoxyphenyl)-3-isopropyl-2-oxo-1,2,3,4-tetrahydropyrazin-yl}methylcarbonylamino-2-hydroxy-4-phenyl-1,1,1-trifluorobutane(Compound No. 3-38)

[1485] IR(Film,cm⁻¹)3324, 3085, 3017, 2966, 2937, 2839, 1670, 1604,1582, 1517, 1465, 1454

[1486] (2RS,3RS)-3-{(3RS)-4-Benzoyl-6-(3,4-dimethoxyphenyl)-3-isopropyl-2-oxo-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-hydroxy-4-phenyl-1,1,1-trifluorobutane(Compound No. 3-39)

[1487] IR(Film,cm⁻¹)3325, 3064, 3023, 2965, 2937, 2839, 1666, 1602,1579, 1517, 1465, 1447

[1488] (2RS,3RS)-3-{(3RS)-6-(3,4-Dimethoxyphenyl)-3-isopropyl-4-methoxymethyl-2-oxo-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-hydroxy-4-phenyl-1,1,1-trifluorobutane(Compound No. 3-40)

[1489] IR(Film,cm⁻¹)3326, 3085, 3013, 2965, 2837, 1677, 1604, 1517, 1453

[1490] (2RS,3RS)-3-{(3RS)-4-Benzoyl-3-isopropyl-6-(3-methoxyphenyl)-2-oxo-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-hydroxy-4-phenyl-1,1,1-trifluorobutane(Compound No. 3-41)

[1491] (2RS,3RS)-3-{(3RS)-4-Acetyl-3-isopropyl-2-oxo-6-(3,4,5-triacetoxyphenyl)-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-hydroxy-4-phenyl-1,1,1-trifluorobutane(Compound No. 3-42)

[1492] (2RS,3RS)-3-{(3RS)-4-Benzoyl-3-isopropyl-2-oxo-6-(3,4,5-triacetoxyphenyl)-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-hydroxy-4-phenyl-1,1,1-trifluorobutane(Compound No. 3-43)

[1493] (2RS,3RS)-3-{(3RS)-4-Acetyl-6-(3,4-diacetoxyphenyl)-3-isopropyl-2-oxo-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-hydroxy-4-phenyl-1,1,1-trifluorobutane(Compound No. 3-44)

[1494] (2RS,3RS)-3-{(3R)-4-Acetyl-6-(3-benzyloxyphenyl)-3-isopropyl-2-oxo-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-hydroxy-4-phenyl-1,1,1-trifluorobutane(Compound No. 3-45)

[1495] IR(Film,cm⁻¹)3311, 1671

[1496] (2RS,3RS)-3-[(3R)-4-Acetyl-6-{3-(3-chlorobenzyloxy)phenyl}-3-isopropyl-2-oxo-1,2,3,4-tetrahydropyrazin-1-yl]methylcarbonylamino-2-hydroxy-4-phenyl-1,1,1-trifluorobutane(Compound No. 3-46)

[1497] IR(Film,cm⁻¹)3317, 1671, 1578, 1492, 1391, 1276

[1498] (2RS,3RS)-3-[(3R)-4-Acetyl-6-{3-(3,5-dichlorobenzyloxy)phenyl}-3-isopropyl-2-oxo-1,2,3,4-tetrahydropyrazin-1-yl]methylcarbonylamino-2-hydroxy-4-phenyl-1,1,1-trifluorobutane(Compound No. 3-47)

[1499] IR(Film,cm⁻¹)3317, 1671, 1432, 1391, 1276, 1213

[1500] (2RS,3RS)-2-{(3RS)-4-Benzoyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-4,4,5,5,6,6,6-heptafluoro-3-hydroxy-1-phenylhexane(Compound No. 3-48)

[1501] IR(Film,cm⁻¹)3318, 3064, 3028, 2967, 1666, 1639, 1548, 1494,1448, 1391

Example 4

[1502](3RS)-3-{(3RS)-4-Acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-oxo-4-phenyl-1,1,1-trifluorobutane(Compound No. 4-1)

[1503] A solution of dimethyl sulfoxide (0.26 ml) in anhydrous methylenechloride (4.0 ml) is cooled with methanol/dry ice, oxalyl chloride (0.16ml) is added to the solution, and the mixture is stirred for 10 minutes.To the mixture is added a solution of (2RS,3RS)-3-{(3RS)-4-acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-hydroxy-4-phenyl-1,1,1-trifluorobutane(0.75 ml, Compound No. 2-1) in anhydrous methylene chloride (3.0 ml).The temperature is raised to 0° C., triethylamine (0.75 ml) is addedthereto, and the whole is stirred for one hour. Ethyl acetate is addedto the reaction mixture, the whole is washed with a saturated aqueousammonium chloride solution and saturated brine successively, and theorganic layer is dried over anhydrous magnesium sulfate. The organiclayer is concentrated under reduced pressure, and the resulting residueis purified by silica gel column chromatography to give the titledcompound (154 mg).

[1504] IR(Film,cm⁻¹)3295, 3088, 1668, 1540

[1505] The following compounds are obtained by a method similar toExample 4.

[1506](3RS)-3-{(3R)-4-Acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-oxo-4-phenyl-1,1,1-trifluorobutane(Compound No. 4-2)

[1507](3RS)-3-{(3S)-4-Acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-oxo-4-phenyl-1,1,1-trifluorobutane(Compound No. 4-3)

[1508](3RS)-3-{4-Acetyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}-methylcarbonylamino-2-oxo-4-phenyl-1,1,1-trifluorobutane(Compound No. 4-4)

[1509](3RS)-3-(4-Acetyl-3,3-dimethyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl)methylcarbonylamino-2-oxo-4-phenyl-1,1,1-trifluorobutane(Compound No. 4-5)

[1510] IR(Film,cm⁻¹)3312, 1755, 1661, 1548, 1495

[1511](3RS)-3-{(3RS)-4-Acetyl-3-ethyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-oxo-4-phenyl-1,1,1-trifluorobutane(Compound No. 4-6)

[1512] IR(Film,cm⁻¹)3323, 3064, 3028, 1672, 1541, 1497

[1513](3RS)-3-[(3RS)-4-Acetyl-3-{(1RS)-1-methylpropyl}-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl]methylcarbonylamino-2-oxo-4-phenyl-1,1,1-trifluorobutane(Compound No. 4-7)

[1514] IR(Film,cm⁻¹)3292, 1784, 1671, 1529, 1496

[1515](3RS)-3-{(3RS)-4-Acetyl-3-isobutyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-oxo-4-phenyl-1,1,1-trifluorobutane(Compound No. 4-8)

[1516] IR(Film,cm⁻¹)3304, 3024, 1782, 1765, 1679, 1646, 1530

[1517](3RS)-3-{(3RS)-4-Acetyl-3-cyclohexyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-oxo-4-phenyl-1,1,1-trifluorobutane(Compound No. 4-9)

[1518] IR(Film,cm⁻¹)3278, 3025, 1785, 1678, 1525, 1448

[1519](3RS)-3-[(3RS)-4-Acetyl-3-{(1RS)-1-tert-butyldimethylsilyloxyethyl}-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl]methylcarbonylamino-2-oxo-4-phenyl-1,1,1-trifluorobutane(Compound No. 4-10)

[1520](3RS)-3-{(3RS)-4-Acetyl-3-methoxymethyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-oxo-4-phenyl-1,1,1-trifluorobutane(Compound No. 4-11)

[1521](3RS)-3-{(3RS)-4-Acetyl-3-(2-methoxyethyl)-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-oxo-4-phenyl-1,1,1-trifluorobutane(Compound No. 4-12)

[1522] IR(Film,cm⁻¹)3316, 3063, 1676, 1541, 1446

[1523](3RS)-3-{(3RS)-4-Acetyl-3,6-diphenyl-2-oxo-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-oxo-4-phenyl-1,1,1-trifluorobutane(Compound No. 4-13)

[1524] IR(Film,cm⁻¹)3271, 3026, 1783, 1679, 1526, 1496, 1447

[1525](3RS)-3-{(3RS)-4-Formyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-oxo-4-phenyl-1,1,1-trifluorobutane(Compound No. 4-14)

[1526] IR(Film,cm⁻¹)3306, 3065, 3026, 2968, 1672, 1656, 1535, 1497, 1447

[1527](3RS)-3-{(3RS)-4-Isobutyryl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-oxo-4-phenyl-1,1,1-trifluorobutane(Compound No. 4-15)

[1528] IR(Film,cm⁻¹)3306, 1763, 1668, 1540

[1529](3RS)-3-{(3R)-4-Isobutyryl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-oxo-4-phenyl-1,1,1-trifluorobutane(Compound No. 4-16)

[1530] IR(Film,cm⁻¹)3305, 1666, 1537

[1531](3RS)-3-{(3RS)-3-Isopropyl-2-oxo-6-phenyl-4-pivaloyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-oxo-4-phenyl-1,1,1-trifluorobutane,(Compound No. 4-17)

[1532] IR(Film,cm⁻¹)3310, 1666, 1540

[1533](3RS)-3-{(3RS)-4-Cyclohexylcarbonyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-oxo-4-phenyl-1,1,1-trifluorobutane(Compound No. 4-18)

[1534] IR(Film,cm⁻¹)3286, 3027, 2934, 2857, 1717, 1673, 1638, 1521, 1449

[1535](3RS)-3-{(3RS)-3-Isopropyl-4-methoxycarbonyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-oxo-4-phenyl-1,1,1-trifluorobutane(Compound No. 4-19)

[1536] IR(Film,cm⁻¹)3305, 3027, 2964, 1784, 1718, 1689, 1522, 1446

[1537](3RS)-3-{(3RS)-4-Ethoxycarbonyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-oxo-4-phenyl-1,1,1-trifluorobutane(Compound No. 4-20)

[1538](3RS)-3-{(3R)-3-Isopropyl-4-methoxyacetyl-9-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-oxo-4-phenyl-1,1,1-trifluorobutane(Compound No. 4-21)

[1539] IR(Film,cm⁻¹)3305, 1678

[1540](3RS)-3-{(3R)-4-Benzoyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-oxo-4-phenyl-1,1,1-trifluorobutane(Compound No. 4-22)

[1541] IR(Film,cm⁻¹)3745, 3471, 3256, 3089, 1689, 1628

[1542](3RS)-3-{(3RS)-4-(4-Chlorobenzoyl)-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-oxo-4-phenyl-1,1,1-trifluorobutane(Compound No. 4-23)

[1543] IR(Film,cm⁻¹)3307, 1666, 1660, 1596

[1544](3RS)-3-{(3RS)-3-Isopropyl-4-(4-methoxybenzoyl)-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-oxo-4-phenyl-1,1,1-trifluorobutane(Compound No. 4-24)

[1545] IR(Film,cm⁻¹)3305, 1665, 1660

[1546](3RS)-3-{(3RS)-3-Isopropyl-4-(4-nitrobenzoyl)-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-oxo-4-phenyl-1,1,1-trifluorobutane(Compound No. 4-25)

[1547](3RS)-3-{(3RS)-3-Isopropyl-2-oxo-6-phenyl-4-(3-phenylpropanoyl)-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-oxo-4-phenyl-1,1,1-trifluorobutane(Compound No. 4-26)

[1548](3RS)-3-{(3RS)-4-Benzyloxycarbonyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-oxo-4-phenyl-1,1,1-trifluorobutane(Compound No. 4-27)

[1549](3RS)-3-{(3RS)-3-Isopropyl-2-oxo-4-phenoxyacetyl-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-oxo-4-phenyl-1,1,1-trifluorobutane(Compound No. 4-28)

[1550] IR(Film,cm⁻¹)3321, 1761, 1677, 1599, 1542, 1495, 1448

[1551](3RS)-3-{(3RS)-3-Isopropyl-2-oxo-6-phenyl-4-(2-thienylcarbonyl)-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-oxo-4-phenyl-1,1,1-trifluorobutane(Compound No. 4-29)

[1552] IR(Film,cm⁻¹)3322, 3085, 3028, 2966, 1782, 1763, 1687, 1628, 1518

[1553](3RS)-3-{(3RS)-3-Isopropyl-2-oxo-6-phenyl-4-(2-pyridylcarbonyl)-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylaminooxo-4-phenyl-1,1,1-trifluorobutane (Compound No. 4-30)

[1554] IR(Film,cm⁻¹)3317, 1670, 1650, 1549

[1555](3RS)-3-{(3RS)-3-Isopropyl-2-oxo-6-phenyl-4-(3-pyridylcarbonyl)-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-oxo-4-phenyl-1,1,1-trifluorobutane(Compound No. 4-31)

[1556] IR(Film,cm⁻¹)3289, 3026, 2967, 1721, 1672, 1644, 1589, 1526,1496, 1446

[1557](3RS)-3-{(3RS)-3-Isopropyl-2-oxo-6-phenyl-4-(4-pyridylcarbonyl)-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-oxo-4-phenyl-1,1,1-trifluorobutane(Compound No. 4-32)

[1558] IR(Film,cm⁻¹)3291, 3025, 2968, 1787, 1679, 1599, 1549, 1495, 1446

[1559](3RS)-3-{(3RS)-3-Isopropyl-4-methanesulfonyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-oxo-4-phenyl-1,1,1-trifluorobutane(Compound No. 4-33)

[1560](3RS)-3-{(3RS)-4-Benzenesulfonyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-oxo-4-phenyl-1,1,1-trifluorobutane(Compound No. 4-34)

[1561] IR(Film,cm⁻¹)3894, 1672, 1447

[1562](3RS)-3-{(3RS)-4-Acetyl-3-isopropyl-2-oxo-6-(3,4,5-trimethoxyphenyl)-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-oxo-4-phenyl-1,1,1-trifluorobutane(Compound No. 4-35)

[1563] IR(Film,cm⁻¹)3314, 3086, 3012, 2968, 2877, 2835, 1671, 1583,1547, 1507, 1455

[1564](3RS)-3-{(3RS)-4-Benzoyl-3-isopropyl-2-oxo-6-(3,4,5-trimethoxyphenyl)-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-oxo-4-phenyl-1,1,1-trifluorobutane(Compound No. 4-36)

[1565] IR(Film,cm⁻¹)3324, 3065, 3012, 2966, 2837, 1665, 1583, 1546,1509, 1453

[1566](3RS)-3-{(3RS)-3-Isopropyl-4-methoxyacetyl-2-oxo-6-(3,4,5-trimethoxyphenyl)-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-oxo-4-phenyl-1,1,1-trifluorobutane(Compound No. 4-37)

[1567] IR(Film,cm⁻¹)3324, 3066, 3010, 2966, 2940, 2830, 1682, 1584,1540, 1507, 1455

[1568](3RS)-3-{(3RS)-4-Acetyl-6-(3,4-dimethoxyphenyl)-3-isopropyl-2-oxo-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-oxo-4-phenyl-1,1,1-trifluorobutane(Compound No. 4-38)

[1569] IR(Film,cm⁻¹)3324, 3085, 3017, 2966, 2937, 2839, 1670, 1604,1582, 1517, 1465, 1454

[1570](3RS)-3-{(3RS)-4-Benzoyl-6-(3,4-dimethoxyphenyl)-3-isopropyl-2-oxo-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-oxo-4-phenyl-1,1,1-trifluorobutane(Compound No. 4-39)

[1571] IR(Film,cm⁻¹)3325, 3064, 3023, 2965, 2937, 2839, 1666, 1602,1579, 1517, 1465, 1447

[1572](3RS)-3-{(3RS)-6-(3,4-dimethoxyphenyl)-3-isopropyl-4-methoxyacetyl-2-oxo-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-oxo-4-phenyl-1,1,1-trifluorobutane(Compound No. 4-40)

[1573] IR(Film,cm⁻¹)3326, 3085, 3013, 2965, 2837, 1677, 1604, 1517, 1453

[1574](3RS)-3-{(3RS)-4-Benzoyl-3-isopropyl-6-(3-methoxyphenyl)-2-oxo-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-oxo-4-phenyl-1,1,1-trifluorobutane(Compound No. 4-41)

[1575](3RS)-3-{(3RS)-4-Acetyl-3-isopropyl-2-oxo-6-(3,4,5-triacetoxyphenyl)-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-oxo-4-phenyl-1,1,1-trifluorobutane(Compound No. 4-42)

[1576](3RS)-3-1{(3RS)-4-Benzoyl-3-isopropyl-2-oxo-6-(3,4,5-triacetoxyphenyl)-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-oxo-4-phenyl-1,1,1-trifluorobutane(Compound No. 4-43)

[1577](3RS)-3-{(3RS)-4-Acetyl-6-(3,4-diacetoxyphenyl)-3-isopropyl-2-oxo-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-oxo-4-phenyl-1,1,1-trifluorobutane(Compound No. 4-44)

[1578](3RS)-3-{(3R)-4-Acetyl-6-(3-benzyloxyphenyl)-3-isopropyl-2-oxo-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-oxo-4-phenyl-1,1,1-trifluorobutane(Compound No. 4-45)

[1579] IR(Film,cm⁻¹)3291, 1682, 1282

[1580](3RS)-3-[(3R)-4-Acetyl-6-{3-(3-chlorobenzyloxy)phenyl}-3-isopropyl-2-oxo-1,2,3,4-tetrahydropyrazin-1-yl]methylcarbonylamino-2-oxo-4-phenyl-1,1,1-trifluorobutane(Compound No. 4-46)

[1581] IR(Film,cm⁻¹)3304, 1670, 1390, 1278

[1582](3RS)-3-[(3R)-4-Acetyl-6-{3-(3,5-dichlorobenzyloxy)phenyl}-3-isopropyl-2-oxo-1,2,3,4-tetrahydropyrazin-1-yl]methylcarbonylamino-2-oxo-4-phenyl-1,1,1-trifluorobutane(Compound No. 4-47)

[1583] [α]_(D) ²⁰ −65.7° (c=0.51, methanol)

[1584] IR(Film,cm⁻¹)3304, 1672, 1571, 1433, 1389, 1286

[1585](2RS)-2-{(3RS)-4-Benzoyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-4,4,5,5,6,6,6-heptafluoro-3-oxo-1-phenylhexane (Compound No. 4-48)

[1586] IR(Film,cm⁻¹)3294, 3063, 3029, 2966, 1689, 1668, 1636, 1577,1538, 1495, 1448, 1388

Example 5

[1587] (1RS,2S)-2-{(3RS)-4-Acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-3-phenyl-1-(1,3-thiazol-2-yl)-1-propanol(Compound No. 5-1)

[1588] N-Methylmorpholine (66.4 μl) is added to a solution of{(3RS)-4-acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}-aceticacid (162 mg, Reference Compound No. 51-1) in tetrahydrofuran (2.5 ml).The mixture is cooled to −10° C., isobutyl chloroformate (65.4 μl) isadded to the mixture, and the whole is stirred for 15 minutes. A mixedsolution of (1RS, 2S)-2-amino-3-phenyl-1-(1,3-thiazol-2-yl)-1-propanolhydrochloride (150 mg, Reference Compound No. 10-2) andN-methylmorpholine (132.6 μl) in tetrahydrofuran (2.5 ml) and dimethylsulfoxide (1 ml) is added thereto, and the whole is stirred overnight.Water is added to the reaction mixture, and the whole is extracted withethyl acetate. The extract is washed with an aqueous sodiumhydrogencarbonate solution, water and saturated brine successively anddried over magnesium sulfate. The extract is concentrated under reducedpressure, and the resulting residue is purified by column chromatographyto give the titled compound (162.9 mg).

[1589] The following compounds are obtained by a method similar toExample 5.

[1590] (1RS,2S)-2-{(3RS)-4-Acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-1-(1,3-benzothiazol-2-yl)-3-phenyl-1-propanol(Compound No. 5-2)

[1591] (1RS,2S)-2-{(3RS)-4-Acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin1-yl}methylcarbonylamino-1-(4,5-dihydro-1,3-oxazol-2-yl)-3-phenyl-1-propanol(Compound No. 5-3)

[1592] IR(Film,cm⁻¹)3307, 3061, 2965, 1749, 1674, 1540, 1446

[1593] (1RS,2S)-2-{(3RS)-4-Acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-1-(4,5-dihydro-1,3-thiazol-2-yl)-3-phenyl-1-propanol(Compound No. 5-4)

[1594] IR(Film,cm⁻¹)3307, 3011, 2965, 1681, 1532, 1446

[1595] (1RS,2S)-1-(4,5-Dihydro-1,3-oxazol-2-yl)-2-{(3RS)-3-isopropyl-4-methoxyacetyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}-methylcarbonylamino-3-phenyl-1-propanol(Compound No. 5-5)

[1596] IR(KBr,cm⁻¹)3324, 3062, 2964, 1746, 1678, 1534, 1496, 1447

[1597] (1RS,2S)-1-(1-Aza-3-oxaspiro[4,4]non-1-en-2-yl)-2-{(3RS)-4-benzoyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}-methylcarbonylamino-3-phenyl-1-propanol(Compound No. 5-6)

[1598] IR(Film,cm⁻¹)3307, 3011, 2965, 1681, 1532, 1446

[1599] (1RS,2S)-1-(1-Aza-3-oxaspiro[4,4]non-1-en-2-yl)-2-{(3RS)-3-isopropyl-4-methoxyacetyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}-methylcarbonylamino-3-phenyl-1-propanol(Compound No. 5-7)

[1600] IR(Film,cm⁻¹)3326, 3062, 3010, 2963, 2874, 1682, 1526, 1447

[1601] (1RS,2S)-1-(4,4-Dimethyl-3,4-dihydro-1,3-oxazol-2-yl)-3-{(3RS)-3-isopropyl-4-methoxyacetyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}-methylcarbonylamino-3-phenyl-1-propanol(Compound No. 5-8)

[1602] IR(Film,cm⁻¹)3323, 3062, 2966, 2932, 1681, 1540, 1450

[1603] (1RS,2S)-2-{(3RS)-4-Benzenesulfonyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-1-(4,4-dimethyl-3,4-dihydro-1,3-oxazol-2-yl)-3-phenyl-1-propanol(Compound No. 5-9)

[1604] IR(Film,cm⁻¹)3368, 3063, 3027, 2967, 2933, 2874, 1682, 1538,1496, 1447

[1605] (1RS,2S)-1-(4,4-Dimethyl-3,4-dihydro-1,3-oxazol-2-yl)-2-{(3RS)-3-isopropyl-2-oxo-6-phenyl-4-pivaloyl-1,2,3,4-tetrahydropyrazin-1-yl}-methylcarbonylamino-3-phenyl-1-propanol(Compound No. 5-10)

[1606] IR(Film,cm⁻¹)3325, 3062, 2968, 2933, 2874, 1665, 1540, 1496, 1446

[1607] (1RS,2S)-2-{(3RS)-4-Acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-1-(5,5-dimethyl-4,5-dihydro-1,3-thiazol-2-yl)-3-phenyl-1-propanol(Compound No. 5-11)

[1608] IR(Film,cm⁻¹)3324, 3011, 2965, 2930, 1682, 1650, 1520, 1446

[1609] (1RS,2S)-1-(5,5-Dimethyl-4,5-dihydro-1,3-thiazol-2-yl)-2-{(3R)-3-isopropyl-2-oxo-6-phenyl-4-(2-pyridylcarbonyl)-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-3-phenyl-1-propanol(Compound No. 5-12)

[1610] IR(Film,cm⁻¹)3326, 3010, 2964, 2928, 1680, 1585, 1568, 1529, 1439

[1611] (1RS,2S)-1-(5,5-Dimethyl-4,5-dihydro-1,3-thiazol-2-yl)-2-{(3RS)-3-isopropyl-2-oxo-6-phenyl-4-(3-pyridylcarbonyl)-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-3-phenyl-1-propanol(Compound No. 5-13)

[1612] IR(Film,cm⁻¹)3330, 3012, 2964, 2930, 1682, 1589, 1520, 1496, 1446

[1613] Isopropyl (2RS,3S)-2-hydroxy-3-{(2RS)-2-isopropyl-3-oxo-3,4-dihydro-2H-1,4-thiazin-4-yl}methylcarbonylamino-4-phenylbutyrate(Compound No. 5-14)

[1614] IR(Film,cm⁻¹)3325, 1732, 1667, 1537, 1495, 1387, 1265

[1615] Isopropyl (2RS,3S)-3-{(2RS)-5-ethyl-2-isopropyl-3-oxo-3,4-dihydro-2H-1,4-thiazin-4-yl}methylcarbonylamino-2-hydroxy-4-phenylbutyrate(Compound No. 5-15)

[1616] IR(Film,cm⁻¹)3393, 1730, 1666, 1529, 1454, 1373, 1263

[1617] Isopropyl (2RS,3S)-2-hydroxy-3-{(2RS)-2-isopropyl-3-oxo-5-phenyl-3,4-dihydro-2H-1,4-thiazin-4-yl}methylcarbonylamino-4-phenylbutyrate(Compound No. 5-16)

[1618] IR(Film,cm⁻¹)3388, 1731, 1672, 1523

[1619] Isopropyl (2RS,3S)-3-{(2RS)-5-(4-fluorophenyl)-2-isopropyl-3-oxo-3,4-dihydro-2H-1,4-thiazin-4-yl}methylcarbonylamino-2-hydroxy-4-phenylbutyrate(Compound No. 5-17)

[1620] IR(Film,cm⁻¹)3369, 1733, 1668, 1508, 1225

[1621] Isopropyl (2RS,3S)-2-hydroxy-3-{(2RS)-2-isopropyl-5-(4-methoxyphenyl)-3-oxo-3,4-dihydro-2H-1,4-thiazin-4-yl}methylcarbonylamino-4-phenylbutyrate(Compound No. 5-18)

[1622] IR(Film,cm⁻¹)3391, 1731, 1667, 1511, 1249

[1623] Isopropyl (2RS,3S)-2-hydroxy-3-{(2RS)-2-methyl-3-oxo-3,4-dihydro-2H-1,4-thiazin-4-yl}methylcarbonylamino-4-phenylbutyrate(Compound No. 5-19)

[1624] IR(Film,cm⁻¹)3409, 1731, 1665, 1539, 1496

[1625] Isopropyl (2RS,3S)-3-{(2RS)-2-ethyl-3-oxo-3,4-dihydro-2H-1,4-thiazin-4-yl}methylcarbonylamino-2-hydroxy-4-phenylbutyrate(Compound No. 5-20)

[1626] IR(Film,cm⁻¹)3328, 3064, 1732, 1667, 1528, 1496, 1454

[1627] Isopropyl (2RS,3S)-2-hydroxy-3-{(2RS)-3-oxo-2-propyl-3,4-dihydro-2H-1,4-thiazin-4-yl}methylcarbonylamino-4-phenylbutyrate(Compound No. 5-21)

[1628] Isopropyl (2RS,3S)-2-hydroxy-3-{(2RS)-2-methoxy-3-oxo-3,4-dihydro-2H-1,4-thiazin-4-yl}methylcarbonylamino-4-phenylbutyrateCompound No. 5-22)

[1629] Isopropyl (2RS,3S)-2-hydroxy-3-[(1RS)-1-{(2RS)-2-isopropyl-3-oxo-3,4-dihydro-2H-1,4-thiazin-4-yl}ethyl]carbonylamino-4-phenylbutyrate(Compound No. 5-23)

[1630] Isopropyl (2RS,3S)-2-hydroxy-3-[(1RS)-1-{(2RS)-2-isopropyl-3-oxo-3,4-dihydro-2H-1,4-thiazin-4-yl}propyl]carbonylamino-4-phenylbutyrate(Compound No. 5-24)

[1631] Isopropyl (2RS,3S)-3-[(1RS)-1-{(2RS)-2-isopropyl-3-oxo-3,4-dihydro-2H-1,4-thiazin-4-yl}-2-phenylethyl]carbonylamino-2-hydroxy-4-phenylbutyrate(Compound No. 5-25)

[1632] (2RS,3S)-3-{(3R)-4-Acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-1-tert-butyldimethylsilyloxy-4-phenyl-2-butanol(Compound No. 5-26)

[1633] IR(Film,cm⁻¹)3325, 2957, 2929, 1674, 1388

[1634] (2RS,3S)-3-{(3RS)-4-Acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}carbonylamino-2-hydroxy-4-phenylbutyramide(Compound No. 5-27)

[1635] N¹-Isopropyl-(2RS,3S)-3-{(3RS)-4-acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-hydroxy-4-phenylbutyramide(Compound No. 5-28)

[1636] IR(Film,cm⁻¹)3307, 1671, 1532

[1637] N¹,N¹-Dimethyl-(2RS,3S)-3-{(3RS)-4-acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-hydroxy-4-phenylbutyramide(Compound No. 5-29)

[1638] IR(Film,cm⁻¹)3326, 2963, 1676, 1535, 1387, 1276

Example 6

[1639](2S)-2-{(3RS)-4-Acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-3-phenyl-1-propanol(Compound No. 6-1)

[1640] N-Methylmorpholine (525 μl), hydroxybenzotriazole (647 mg) andL-phenylalaninol (491 mg) are added to a solution of{(3RS)-4-acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}aceticacid (1.01 g, Reference Compound No. 51-1) in methylene chloride (25ml). The mixture is cooled with ice,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride is added tothe mixture, and the whole is stirred for three days. Ethyl acetate isadded to the reaction mixture, and the whole is washed with a 0.1 Naqueous sodium hydroxide solution, saturated brine, 1 N hydrochloricacid and saturated brine successively. The organic layer is dried overanhydrous magnesium sulfate and concentrated under reduced pressure, andthe resulting residue is purified by silica gel column chromatography togive the titled compound (1.37 g).

[1641] IR(Film,cm⁻¹)3318, 2963, 1670, 1540

[1642] The following compounds are obtained by a method similar toExample 6.

[1643](2S)-2-{(3RS)-4-Isobutyryl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-3-phenyl-1-propanol(Compound No. 6-2)

[1644] IR(Film,cm⁻¹)3325, 1668, 1540

[1645](2S)-2-{(3R)-4-Isobutyryl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-3-phenyl-1-propanol(Compound No. 6-3)

[1646](2S)-2-{(3RS)-4-Benzoyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-3-phenyl-1-propanol(Compound No. 6-4)

[1647] IR(Film,cm⁻¹)3325, 1667, 1660

[1648](2S)-2-{(3R)-3-Isopropyl-2-oxo-6-phenyl-4-(4-pyridylcarbonyl)-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-3-phenyl-1-propanol(Compound No. 6-5)

[1649] [α]_(D) ²⁰ −121.6° (c=0.54, dimethyl sulfoxide)

[1650] IR(KBr,cm⁻¹)3288, 1691, 1674, 1645, 1601, 1552

[1651](2S)-2-{(3R)-3-Isopropyl-2-oxo-6-phenyl-4-(3-pyridylcarbonyl)-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-3-phenyl-1-propanol(Compound No. 6-6)

[1652] [α]_(D) ²⁰ −121.70 (c=0.97, methanol)

[1653] IR(Film,cm⁻¹)3327, 2962, 2927, 1669, 1644, 1446

[1654](2S)-2-{(3RS)-3-Isopropyl-2-oxo-6-phenyl-4-(2-pyridylcarbonyl)-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-3-phenyl-1-propanol(Compound No. 6-7)

[1655] IR(Film,cm⁻¹)3327, 1669

[1656](2S)-2-{(3R)-3-Isopropyl-2-oxo-6-phenyl-4-(2-pyridylcarbonyl)-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-3-phenyl-1-propanol(Compound No. 6-8)

[1657] [α]_(D) ²⁰ −185.0° (c=1.0, methanol)

[1658] IR(Film,cm⁻¹)3326, 1670, 1441

[1659](2S)-2-{(3R)-4-Acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-3-phenyl-1-propanol(Compound No. 6-9)

[1660] [α]_(D) ²⁰ −97.1° (c=1.0, methanol)

[1661] IR(Film,cm⁻¹)3321, 1670, 1548, 1391

Example 7

[1662](2S)-2-{(3RS)-4-Acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-3-phenylpropanal(Compound No. 7-1)

[1663] Triethylamine (2.60 ml) is added to a solution of(2S)-2-{(3RS)-4-acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}-methylcarbonylamino-3-phenyl-1-propanol(1.37 g, Compound No. 6-1) in dimethyl sulfoxide (16 ml). A sulfurtrioxide-pyridine complex (1.7 g) is added to the mixture, and the wholeis stirred overnight. Water is added to the reaction mixture, and thewhole is stirred for one hour and extracted with ethyl acetate. Theextract is washed with a saturated aqueous ammonium chloride solution,water and saturated brine successively and dried over anhydrousmagnesium sulfate. The extract is concentrated under reduced pressure,and the resulting residue is purified by silica gel columnchromatography to give the titled compound (631 mg).

[1664] IR(Film,cm⁻¹)3306, 3025, 2964, 1735, 1673, 1538

[1665] The following compounds are obtained by a method similar toExample 7.

[1666](2S)-2-{(3RS)-4-Isobutyryl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-3-phenylpropanal(Compound No. 7-2)

[1667](2S)-2-{(3R)-4-Isobutyryl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-3-phenylpropanal(Compound No. 7-3)

[1668](2S)-2-{(3RS)-4-Benzoyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-3-phenylpropanal(Compound No. 7-4)

[1669] IR(Film,cm⁻¹)3311, 1734, 1668

[1670](2S)-2-{(3R)-3-Isopropyl-2-oxo-6-phenyl-4-(4-pyridylcarbonyl)-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-3-phenylpropanal(Compound No. 7-5)

[1671](2S)-2-{(3R)-3-Isopropyl-2-oxo-6-phenyl-4-(3-pyridylcarbonyl)-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-3-phenylpropanal(Compound No. 7-6)

[1672] [α]_(D) ²⁰ −106.50 (c=0.99, chloroform)

[1673] IR(Film,cm⁻¹)3326, 2963, 2925, 1668, 1643, 1588, 1539, 1446

[1674](2S)-2-{(3RS)-3-Isopropyl-2-oxo-6-phenyl-4-(2-pyridylcarbonyl)-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-3-phenylpropanal(Compound No. 7-7)

[1675](2S)-2-{(3R)-3-Isopropyl-2-oxo-6-phenyl-4-(2-pyridylcarbonyl)-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-3-phenylpropanal(Compound No. 7-8)

[1676] [α]_(D) ²⁰ −175.8°. (c=1.0, chloroform)

[1677] IR(Film,cm⁻¹) 1734, 1682, 1437

[1678](2S)-2-{(3R)-4-Acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-3-phenylpropanal(Compound No. 7-9)

[1679] [α]_(D) ²⁰ −102.10 (c=0.93, methanol)

[1680] IR(Film,cm⁻¹)3308, 1740

[1681](3S)-3-{(3R)-4-Acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-1-tert-butyldimethylsilyloxy-2-oxo-4-phenylbutane(Compound No. 7-10)

[1682] IR(Film,cm⁻¹)3307, 2930, 2856, 1680, 1528, 1388

Example 8

[1683] (2RS,3S)-3-{(3RS)-4-Acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-hydroxy-4-phenylbutanenitrile(Compound No. 8-1)

[1684](2S)-2-{(3RS)-4-Acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-3-phenylpropanal(630 mg, Compound No. 7-1) is suspended in water (6 ml). Sodiumhydrogensulfite (160 mg), water (6 ml) and ethyl acetate (18 ml) areadded to the suspension, and the mixture is stirred for 30 minutes.Potassium cyanide (105 mg) is added to the mixture, and the whole isstirred for one day. Water is added to the reaction mixture, and thewhole is extracted with ethyl acetate. The extract is washed with waterand saturated brine successively and dried over anhydrous magnesiumsulfate. The extract is concentrated under reduced pressure, and theresulting residue is purified by silica gel column chromatography togive the titled compound (624 mg).

[1685] IR(Film,cm⁻¹)3305, 1669, 1540

[1686] The following compounds are obtained by a method similar toExample 8.

[1687] (2RS,3S)-2-Hydroxy-3-{(3RS)-4-isobutyryl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-4-phenylbutanenitrile(Compound No. 8-2)

[1688] IR(Film,cm⁻¹)3308, 1670

[1689] (2RS,3S)-2-Hydroxy-3-{(3R)-4-isobutyryl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-4-phenylbutanenitrile(Compound No. 8-3)

[1690] IR(Film,cm⁻¹)3310, 1666, 1536, 1446

[1691] (2RS,3S)-3-{(3RS)-4-Benzoyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-hydroxy-4-phenylbutanenitrile(Compound No. 8-4)

[1692] IR(Film,cm⁻¹)3306, 1666, 1447

[1693] (2RS,3S)-2-Hydroxy-3-{(3R)-3-isopropyl-2-oxo-6-phenyl-4-(4-pyridylcarbonyl)-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-4-phenylbutanenitrile(Compound No. 8-5)

[1694] IR(Film,cm⁻¹)3310, 1672, 1601, 1551, 1495, 1446

[1695] (2RS,3S)-2-Hydroxy-3-{(3R)-3-isopropyl-2-oxo-6-phenyl-4-(3-pyridylcarbonyl)-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-4-phenylbutanenitrile(Compound No. 8-6)

[1696] IR(Film,cm⁻¹)3356, 2956, 1662, 1648, 1540, 1450, 1426

[1697] (2RS,3S)-2-Hydroxy-3-{(3RS)-3-isopropyl-2-oxo-6-phenyl-4-(2-pyridylcarbonyl)-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-4-phenylbutanenitrile(Compound No. 8-7)

[1698] IR(Film,cm⁻¹)3306, 1672

[1699] (2RS,3S)-2-Hydroxy-3-{(3R)-3-isopropyl-2-oxo-6-phenyl-4-(2-pyridylcarbonyl)-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-4-phenylbutanenitrile(Compound No. 8-8)

[1700] IR(Film,cm⁻¹)3314, 1672, 1643

Example 9

[1701] (1RS,2S)-2-{(3RS)-4-Acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-1-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-3-phenyl-1-propanol(Compound No. 9-1)

[1702] Acetyl chloride (1.1 ml) is added dropwise to a solution ofethanol (0.95 ml) in chloroform (2 ml) under ice cooling. Then, to themixture is added a solution of (2RS,3S)-3-{(3RS)-4-acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-hydroxy-4-phenylbutanenitrile(250 mg, Compound No. 8-1) in chloroform (3 ml), and the whole isstirred for one hour. The reaction mixture is concentrated under reducedpressure, ethanol (4 ml) and 2-amino-2-methyl-1-propanol (75 μl) areadded to the resulting residue, and the whole is refluxed for one day.The reaction mixture is allowed to stand at room temperature, ethylacetate is added to the reaction mixture, and the whole is washed withsaturated brine. The organic layer is dried over anhydrous magnesiumsulfate and concentrated under reduced pressure, and the resultingresidue is purified by silica gel column chromatography to give thetitled compound (113 mg).

[1703] IR(Film,cm⁻¹)3307, 1674

[1704] The following compounds are obtained by a method similar toExample 9.

[1705] (1RS,2S)-1-(4,4-Dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-2-{(3RS)-4-isobutyryl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}-methylcarbonylamino-3-phenyl-1-propanol(Compound No. 9-2)

[1706] IR(Film,cm⁻¹)3319, 1674, 1536

[1707] (1RS,2S)-1-(4,4-Dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-2-{(3R)-4-isobutyryl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}-methylcarbonylamino-3-phenyl-1-propanol(Compound No. 9-3)

[1708] IR(Film,cm⁻¹)3318, 1674, 1536

[1709] (1RS,2S)-1-(5,5-Dimethyl-4,5-dihydro-1,3-thiazol-2-yl)-2-{(3RS)-4-isobutyryl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}-methylcarbonylamino-3-phenyl-1-propanol(Compound No. 9-4)

[1710] IR(Film,cm⁻¹)3324, 2968, 2932, 1682, 1446

[1711] (1RS,2S)-1-(5,5-Dimethyl-4,5-dihydro-1,3-thiazol-2-yl)-2-{(3R)-4-isobutyryl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}-methylcarbonylamino-3-phenyl-1-propanol(Compound No. 9-5)

[1712] IR(Film,cm⁻¹)3324, 2967, 1682, 1522, 1446

[1713] (1RS,2S)-1-(1-Aza-3-oxaspiro[4,4]non-1-en-2-yl)-2-{(3RS)-4-isobutyryl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}-methylcarbonylamino-3-phenyl-1-propanol(Compound No. 9-6)

[1714] IR(Film,cm⁻¹)3325, 1671, 1538

[1715] (1RS,2S)-2-{(3RS)-4-Benzoyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-1-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-3-phenyl-1-propanol(Compound No. 9-7)

[1716] IR(Film,cm⁻¹)3309, 1668

[1717] (1RS,2S)-2-{(3RS)-4-Benzoyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-1-(5,5-dimethyl-4,5-dihydro-1,3-thiazol-2-yl)-3-phenyl-1-propanol(Compound No. 9-8)

[1718] (1RS,2S)-1-(4,4-Dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-2-{(3R)-3-isopropyl-2-oxo-6-phenyl-4-(4-pyridylcarbonyl)-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-3-phenyl-1-propanol(Compound No. 9-9)

[1719] IR(Film,cm⁻¹)3291, 1673, 1599, 1551, 1446

[1720] (1RS,2S)-1-(5,5-Dimethyl-4,5-dihydro-1,3-thiazol-2-yl)-2-{(3R)-3-isopropyl-2-oxo-6-phenyl-4-(4-pyridylcarbonyl)-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-3-phenyl-1-propanol(Compound No. 9-10)

[1721] IR(Film,cm⁻¹)3324, 1682, 1650, 1552

[1722] (1RS,2S)-1-(4,4-Dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-2-{(3R)-3-isopropyl-2-oxo-6-phenyl-4-(3-pyridylcarbonyl)-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-3-phenyl-1-propanol(Compound No. 9-11)

[1723] IR(Film,cm⁻¹)3324, 2966, 1673, 1644

[1724] (1RS,2S)-1-(4,4-Dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-2-{(3RS)-3-isopropyl-2-oxo-6-phenyl-4-(2-pyridylcarbonyl)-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-3-phenyl-1-propanol(Compound No. 9-12)

[1725] IR(Film,cm⁻¹)3321, 1672

[1726] (1RS,2S)-1-(4,4-Dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-2-{(3R)-3-isopropyl-2-oxo-6-phenyl-4-(2-pyridylcarbonyl)-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-3-phenyl-1-propanol(Compound No. 9-13)

[1727] IR(Film,cm⁻¹)3324, 1673, 1539, 1437

Example 10

[1728](2S)-2-{(3RS)-4-Acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-1-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-1-oxo-3-phenylpropane(Compound No. 10-1)

[1729] Dess-Martin oxidizing reagent (293 mg) and tert-butanol (650 μl)are added to a solution of (1RS,2S)-2-{(3RS)-4-acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-1-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-3-phenyl-1-propanol(93.3-mg, Compound No. 9-1) in methylene chloride (2.5 ml), and themixture is stirred for one day. A saturated aqueous sodiumhydrogencarbonate solution (6 ml) and an aqueous sodium thiosulfatesolution (6 ml) are added to the reaction mixture, and the whole isstirred and then extracted with ethyl acetate. The extract is washedwith an aqueous sodium thiosulfate solution, a saturated aqueous sodiumhydrogencarbonate solution and saturated brine successively and driedover anhydrous magnesium sulfate. The extract is concentrated underreduced pressure, and the resulting residue is purified by silica gelcolumn chromatography to give the titled compound (43.8 mg).

[1730] IR(Film,cm⁻¹)3306, 1682, 1520

[1731] The following compounds are obtained by a method similar toExample 10.

[1732](2S)-1-(4,4-Dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-2-{(3RS)-4-isobutyryl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}-methylcarbonylamino1-oxo-3-phenylpropane (Compound No. 10-2)

[1733] IR(Film,cm⁻¹)3324, 1700, 1678

[1734](2S)-1-(4,4-Dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-2-{(3R)-4-isobutyryl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}-methylcarbonylamino-1-oxo-3-phenylpropane(Compound No. 10-3)

[1735] IR(Film,cm⁻¹)3323, 1726, 1682, 1518

[1736](2S)-1-(5,5-Dimethyl-4,5-dihydro-1,3-thiazol-2-yl)-2-{(3RS)-4-isobutyryl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}-methylcarbonylamino-1-oxo-3-phenylpropane(Compound. No. 10-4)

[1737] IR(Film,cm⁻¹)2967, 1681, 1516, 1446

[1738](2S)-1-(5,5-Dimethyl-4,5-dihydro-1,3-thiazol-2-yl)-2-{(3R)-4-isobutyryl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}-methylcarbonylamino-1-oxo-3-phenylpropane(Compound No. 10-5)

[1739] [α]_(D) ²⁰ −80.80 (c=1.0, dimethyl sulfoxide)

[1740] IR(Film,cm⁻¹)3325, 2967, 1682, 1646, 1314, 1446

[1741] (2S)-1-(1-Aza-3-oxaspiro[4,4]non-1-en-2-yl)-2-{(3RS)-4-isobutyryl-3isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-1-oxo-3-phenylpropane(Compound No. 10-6)

[1742] IR(Film,cm⁻¹)3323, 1678

[1743](2S)-2-{(3RS)-4-Benzoyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-1-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-1-oxo-3-phenylpropane(Compound No. 10-7)

[1744] IR(Film,cm⁻¹)3320, 1727, 1684, 1578

[1745](2S)-2-{(3RS)-4-Benzoyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-1-(5,5-dimethyl-4,5-dihydro-1,3-thiazol-2-yl)-2-oxo-3-phenylpropane(Compound No. 10-8)

[1746](2S)-1-(4,4-Dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-2-{(3R)-3-isopropyl-2-oxo-6-phenyl-4-(4-pyridylcarbonyl)-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-1-oxo-3-phenylpropane(Compound No. 10-9)

[1747](2S)-1-(5,5-Dimethyl-4,5-dihydro-1,3-thiazol-2-yl)-2-{(3R)-3-isopropyl-2-oxo-6-phenyl-4-(4-pyridylcarbonyl)-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-1-oxo-3-phenylpropane (Compound No. 10-10)

[1748] mp 100.0-125.0° C.

[1749] [α]_(D) ²⁰ −107.80 (c=1.0, methanol)

[1750] IR(KBr,cm⁻¹)3218, 1684

[1751](2S)-1-(4,4-Dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-2-{(3R)-3-isopropyl-2-oxo-6-phenyl-4-(3-pyridylcarbonyl)-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-1-oxo-3-phenylpropane (Compound No. 10-11)

[1752] [α]_(D) ²⁰ 104.9° (c=1.0, dimethyl sulfoxide)

[1753] IR(Film,cm⁻¹)3325, 3023, 2969, 1723, 1678, 1642, 1589, 1517, 1447

[1754](2S)-1-(4,4-Dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-2-{(3RS)-3-isopropyl-2-oxo-6-phenyl-4-(2-pyridylcarbonyl)-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-1oxo-3-phenylpropane (Compound No. 10-12)

[1755] IR(Film,cm⁻¹)3324, 1736, 1681, 1514

[1756](2S)-1′-(4,4-Dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-2-{(3R)-3-isopropyl-2-oxo-6-phenyl-4-(2-pyridylcarbonyl)-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-1-oxo-3-phenylpropane (Compound No. 10-13)

[1757] [α]_(D) ²⁰ −126.6° (c=0.98, dimethyl sulfoxide)

[1758] IR(Film,cm⁻¹)3324, 3061, 3014, 2970, 2934, 11737, 1682, 1641,1586, 1568, 1514, 1468

[1759](2S)-{(3RS)-4-Acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}-1-oxo-3-phenyl-1-(1H-1,2,3,4-tetrazol-5-yl)-propane(Compound No. 10-14)

[1760] IR(Film,cm⁻¹)3204, 1673, 1529, 1391, 756

Example 11

[1761](3S)-3-{(3R)-4-Acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-oxo-4-phenylbutyricacid (Compound No. 11-1)

[1762] Water (0.45 ml) and a 1 N aqueous lithium hydroxide solution (55μl) are added to a solution of isopropyl(3S)-3-{(3R)-4-acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-oxo-4-phenylbutyrate(24.5 mg, Compound No. 2-2) in methanol (0.5 ml), and the mixture isstirred for one hour. The reaction mixture is concentrated under reducedpressure, and 1 N hydrochloric acid is added to the concentrate toacidify the system. The whole is extracted with ethyl acetate, and theextract is washed with water and a saturated aqueous sodiumhydrogencarbonate solution successively and dried over magnesiumsulfate. The extract is concentrated under reduced pressure, and theresulting residue is purified by silica gel column chromatography togive the titled compound (21.8 mg).

[1763] IR(KBr,cm⁻¹)3305, 2965, 1671, 1534, 1497, 1389

Example 12

[1764](3S)-3-{(3R)-4-Acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-oxo-4-phenyl-1-butanol(Compound No. 12-1)

[1765] A 1.0 M tetrabutylammonium fluoride/tetrahydrofuran solution (0.5ml) is added to a solution of(3S)-3-{(3R)-4-acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-1-tert-butyldimethylsilyloxy-2-oxo-4-phenylbutane(130 mg, Compound No. 7-10) in tetrahydrofuran (0.5 ml), and the mixtureis stirred for 2.5 hours. The reaction mixture is concentrated underreduced pressure, and the resulting residue is purified by silica gelcolumn chromatography to give the titled compound (25.2 mg).

[1766] IR(Film,cm⁻¹)3849, 3305, 2963, 1674, 1529, 1388

Example 13

[1767](2S)-2-{(3RS)-4-Acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-3-phenylpropionicacid (Compound No. 13-1)

[1768] A 4 N aqueous sodium hydroxide solution (7.2 ml) is added to asolution of methyl(2S)-2-{(3RS)-4-acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-3-phenylpropionate(4.60 g, Compound No. 1-48) in ethanol (30 ml), and the mixture isstirred for 4.5 hours. The reaction mixture is washed with ether, then 2N hydrochloric acid is added to the reaction mixture to acidify thesystem, and the whole is extracted with ethyl acetate. The extract iswashed with saturated brine and dried over anhydrous magnesium sulfate.The extract is concentrated under reduced pressure to give the titledcompound (4.46 g).

[1769] IR(Film,cm⁻¹)3306, 3016, 1732, 1679, 1530, 1446, 1391

Example 14

[1770] 4-Nitrophenyl(2S)-2-{(3RS)-4-acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-3-phenylpropionate(Compound No. 14-1)

[1771] 4-Nitrophenol (1.39 g) and dicydohexylcarbodiimide (2.01 g) areadded to a solution of(2S)-2-{(3RS)-4-acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-3-phenylpropionicacid (4.30 g, Compound No. 13-1) in ethyl acetate (100 ml), and themixture is stirred overnight. The resulting impurity is filtered out,then the filtrate is concentrated under reduced pressure, and theresulting residue is purified by silica gel column chromatography togive the titled compound (4.52 g).

[1772] IR(Film,cm⁻¹)3303, 3025, 1769, 1679, 1592, 1524, 1491, 1446, 1390

Example 15

[1773]3-[(2S)-2-{(3RS)-4-Acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-3-phenylpropanoyl]-1-methylhydantoin(Compound No. 15-1)

[1774] 60% Sodium hydride (200 mg) is added to a solution of1-methylhydantoin (571 mg) in anhydrous tetrahydrofuran (20 ml), and themixture is stirred for 20 minutes. Then, 4-nitrophenyl(2S)-2-{(3RS)-4-acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-3-phenylpropionate(1.17 g, Compound No. 14-1) is added to the mixture, and the whole isstirred for three days. A saturated aqueous ammonium chloride solutionis added to the reaction mixture, and the whole is extracted with ethylacetate. The extract is washed with a saturated aqueous sodiumhydrogencarbonate solution and saturated brine successively and driedover anhydrous magnesium sulfate. The extract is concentrated underreduced pressure, and the resulting residue is purified by silica gelcolumn chromatography to give the titled compound (116 mg).

[1775] IR(Film,cm⁻¹)3303, 3016, 2966, 2935, 1739, 1526, 1417, 1391

Example 16

[1776](2S)-2-{(3RS)-4-Acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-1-(2,3-dihydrofuran-5-yl)-1-oxo-3-phenylpropane(Compound No. 16-1)

[1777] A solution of 2,3-dihydrofuran (80 μl) in anhydroustetrahydrofuran (2 ml) is cooled to −78° C., a 1.55 Ntert-butyllithium/pentane solution (660 μl) is added thereto, and themixture is stirred for one hour. The mixture is added to a solution ofN¹-methoxy-N¹-methyl-(2S)-2-{(3RS)-4-acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-3-phenylpropionamide(295 mg, Compound No. 1-51) in anhydrous tetrahydrofuran (3 ml) cooledat −78° C., and the whole is stirred for two hours. The temperature israised to 0° C., and the reaction mixture is stirred for 30 minutes. Asaturated aqueous ammonium chloride solution is added to the reactionmixture, and the whole is extracted with ethyl acetate. The extract iswashed with saturated brine and dried over anhydrous magnesium sulfate.The extract is concentrated under reduced pressure, and the resultingresidue is purified by silica gel column chromatography to give thetitled compound (38.4 mg).

[1778] IR(Film,cm⁻¹)3307, 1679, 1388

Example 17

[1779](3S)-3-{(3RS)-4-Acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-oxo-4-phenylbutane(Compound No. 17-1)

[1780] A solution ofN¹-methoxy-N¹-methyl-(2S)-2-{(3RS)-4-acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}-methylcarbonylamino-3-phenylpropionamide(122 mg, Compound No. 1-51) in anhydrous tetrahydrofuran (2 ml) iscooled to −78° C., a 1.0 M methyllithium/tetrahydrofuran/cumene solution(1.2 ml) is added thereto, and the mixture is stirred for 15 minutes. Asaturated aqueous ammonium chloride solution is added to the reactionmixture, and the temperature is raised to 0° C. The whole is extractedwith ethyl acetate, and the extract is washed with saturated brine anddried over anhydrous magnesium sulfate. The extract is concentratedunder reduced pressure, and the resulting residue is purified by silicagel column chromatography to give the titled compound (53.8 mg).

[1781] IR(Film,cm⁻¹)3305, 1700, 1660

Example 18

[1782] (2RS,3S)-2-Acetoxy-3-{(3RS)-4-acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-4-phenylbutanenitrile(Compound No. 18-1)

[1783] Pyridine (0.15 ml) is added to a solution of (2RS,3S)-3-{(3RS)-4-acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}-methylcarbonylamino-2-hydroxy-4-phenylbutanenitrile(291 mg, Compound No. 8-1) in methylene chloride (3 ml). The mixture iscooled with ice, acetic anhydride (115 μl) and dimethylaminopyridine(catalytic amount) are added to the mixture, and the whole is stirredfor six hours. Ethyl acetate is added to the reaction mixture and thewhole is washed with 1 N hydrochloric acid and saturated brinesuccessively. The organic layer is concentrated under reduced pressure,and the resulting residue is purified by silica gel columnchromatography to give the titled compound (317 mg).

[1784] IR(Film,cm⁻¹)3305, 1758,1682, 1538, 1388, 1320, 1275, 757

Example 19

[1785] (1RS,2S)-2-{(3RS)-4-Acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}-3-phenyl-1-(1H-1,2,3,4-tetrazol-5-yl)-1-propanol(Compound No. 19-1)

[1786] Sodium azide (75.3 mg) and aluminum chloride (386 mg) are addedto a solution of (2RS,3S)-2-acetoxy-3-{(3RS)-4-acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-4-phenylbutanenitrile(299 mg, Compound No. 18-1) in tetrahydrofuran (3.5 ml), and the mixtureis stirred for two hours. The reaction mixture is warmed to 60° C. andstirred for three hours. The reaction mixture is cooled to roomtemperature, then water is added to the reaction mixture, and the wholeis extracted with ethyl acetate. The extract is washed with saturatedbrine and dried over anhydrous magnesium sulfate. The extract isconcentrated under reduced pressure, and the resulting residue ispurified by silica gel column chromatography to give the titled compound(242 mg).

[1787] IR(Film,cm⁻¹)3292, 1667, 1529, 1391, 756

Example 20

[1788](2S)-2-{(3RS)-3-Isopropyl-2-oxo-4-methoxyacetyl-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-1-oxo-1-(piperazin-1-yl)-3-phenylpropanehydrochloride (Compound No. 20-1)

[1789] A 4 N hydrogen chloride/ethyl acetate solution (0.24 ml) is addedto a solution of(2S)-1-(4-tert-butoxycarbonylpiperazin-1-yl)-2-{(3RS)-3-isopropyl-4-methoxyacetyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-1-oxo-3-phenylpropane(190 mg, Compound No. 1-55) in ethyl acetate (3 ml), and the mixture isstirred for one hour. The reaction mixture is concentrated under reducedpressure to give the titled compound (146 mg).

[1790] mp 120° C.

[1791] IR(Film,cm⁻¹)3450, 2963, 1684, 1652, 1544, 1496, 1448, 1389

Example 21

[1792]3-[(2R)-4-{(1S)-1-Benzyl-2-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-2-oxoethylcarbamoylmethyl}-2-isopropyl-3-oxo-5-phenyl-1,2,3,4-tetrahydro-1-pyrazinylcarbonyl]-1-methylpyridiniumiodide (Compound No. 21-1)

[1793] Methyl iodide (246 μl) is added to a solution of(2S)-1-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-2-{(3R)-3-isopropyl-2-oxo-6-phenyl-4-(3-pyridylcarbonyl)-1,2,3,4-tetrahydropyrazin-1-yl}-methylcarbonylamino-1-oxo-3-phenylpropane(80 mg) in acetonitrile (2 ml), and the mixture is stirred overnight.The reaction mixture is concentrated under reduced pressure, andacetonitrile/diethyl ether is added to the resulting residue toprecipitate crystals. The precipitated crystals are filtered off to givethe titled compound (75 mg).

[1794] mp 160.0° C.

[1795] [α]_(D) ²⁰ −106.4° (c=1.0, dimethyl sulfoxide)

[1796] IR(KBr,cm⁻¹)3421, 3050, 2967, 1726, 1676, 1447

[1797] The following compounds are obtained by a method similar toExample 21.

[1798]3-[(2R)-4-{(1S)-1-Benzyl-2-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-oxoethylcarbamoylmethyl}-2-isopropyl-3-oxo-5-phenyl-1,2,3,4-tetrahydro-1-pyrazinylcarbonyl]-1-methoxycarbonylmethylpyridiniumbromide (Compound No. 21-2)

[1799] mp 140.0° C.

[1800] [α]_(D) ²⁰ −113.1° (c=1.0, dimethyl sulfoxide)

[1801] IR(KBr,cm⁻¹)3350, 3200, 3030.2968, 1755, 1675, 1542, 1447

[1802]1-Benzyl-3-[(2R)-4-{(1S)-1-benzyl-2-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-2-oxoethylcarbamoylmethyl}-2-isopropyl-3-oxo-5-phenyl-1,2,3,4-tetrahydro-1-pyrazinylcarbonyl]pyridiniumbromide (Compound No. 21-3)

[1803] mp 135-150° C.

[1804] [α]_(D) ²⁰ −110.10 (c=1.0, dimethyl sulfoxide)

[1805] IR(KBr,cm⁻¹)3400, 3188, 3031, 2966, 1725, 1674, 1455, 1446

[1806]3-[(2R)-4-{(1S)-1-Benzyl-2-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-2-oxoethylcarbamoylmethyl}-2-isopropyl-3-oxo-5-phenyl-1,2,3,4-tetrahydro-1-pyrazinylcarbonyl]-1-carbamoylmethylpyridiniumbromide (Compound No. 21-4)

[1807] mp 110.0° C.

[1808] [α]_(D) ²⁰ −103.10 (c=0.98, dimethyl sulfoxide)

[1809] IR(KBr,cm⁻¹)3165, 2968, 1674

[1810]3-[(2R)-4-{(1S)-1-Benzyl-2-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl-2-oxoethylcarbamoylmethyl}-2-isopropyl-3-oxo-5-phenyl-1,2,3,4-tetrahydro-1-pyrazinylcarbonyl]-1-[(E,E)-3,7,11-trimethyl-2,6,10-dodecathorin-1-yl]pyridinium bromide(Compound No. 21-5)

[1811] mp95-120° C.

[1812] [α]_(D) ²⁰ −79.9° (c=0.99, dimethyl sulfoxide)

[1813] IR(KBr,cm⁻¹)3198, 2965, 1679, 1518, 1446

[1814]3-[(2RS)-4-{(1RS)-1-Benzyl-2-oxo-3,3,3-trifluoropropylcarbamoylmethyl}-2-isopropyl-3-oxo-5-phenyl-1,2,3,4-tetrahydro-1-pyrazinylcarbonyl]-1-methylpyridiniumiodide (Compound No. 21-6)

[1815] IR(KBr,cm⁻¹)3436, 1785, 1677, 1447

[1816]4-[(2RS)-4-{(1RS)-1-Benzyl-2-oxo-3,3,3-trifluoropropylcarbamoylmethyl}-2-isopropyl-3-oxo-5-phenyl-1,2,3,4-tetrahydro-1-pyrazinylcarbonyl]-1-methylpyridiniumiodide (Compound No. 21-7)

[1817] IR(KBr,cm⁻¹)3428, 1786, 1682

[1818]4-[(2R)-4-{(1S)-1-Benzyl-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-2-oxopropylcarbamoylmethyl}-2-isopropyl-3-oxo-5-phenyl-1,2,3,4-tetrahydro-1-pyrazinylcarbonyl]-1-methyloxycarbonylmethylpyridiniumbromide (Compound No. 21-8)

[1819] IR(KBr,cm⁻¹)3856, 1753, 1677

[1820]1-Benzyl-4-[(2R)-4-{(1S)-1-benzyl-2-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-2-oxoethylcarbamoylmethyl}-2-isopropyl-3-oxo-5-phenyl-1,2,3,4-tetrahydro-1-pyrazinylcarbonyl]pyridiniumbromide (Compound No. 21-9)

[1821] IR(KBr,cm⁻¹)3369, 1730, 1677

[1822]4-[(2R)-4-{(1S)-1-Benzyl-2-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-2-oxoethylcarbamoylmethyl}-2-isopropyl-3-oxo-5-phenyl-1,2,3,4-tetrahydro-1-pyrazinylcarbonyl]-1-(3-methyl-2-butenyl)pyridiniumbromide (Compound No. 21-10)

[1823] IR(KBr,cm⁻¹)3600-2000, 1742, 1677

[1824]4-[(2R)-4-{(1S)-1-Benzyl-2-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-2-oxoethylcarbamoylmethyl}-2-isopropyl-3-oxo-5-phenyl-1,2,3,4-tetrahydro-1-pyrazinylcarbonyl]-1-{(2E)-3,7-dimethyl-2,6-octadienyl}-pyridiniumbromide (Compound No. 21-11)

[1825] IR(KBr,cm⁻¹)3560-2300, 1752, 1676, 1529

[1826]4-{(2R)-4-[(1S)-1-Benzyl-2-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)-2-oxoethylcarbamoylmethyl]-2-isopropyl-3-oxo-5-phenyl-1,2,3,4-tetrahydro-1-pyrazinylcarbonyl}-1-(carbamoylmethyl)pyridiniumiodide (Compound No. 21-12)

[1827] mp78.0-85.0° C.

[1828] IR(KBr,cm⁻¹)3305, 1671

[1829] Formulation

[1830] General formulation examples of oral preparations and eyedropsusing the present compounds are shown below.

[1831] 1) Tablet Formulation 1 in 100 mg Present compound 1 mg Lactose66.4 mg Cornstarch 20 mg Calcium carboxymethylcellulose 6 mgHydroxypropylcellulose 4 mg Magnesium stearate 0.6 mg

[1832] Tablets according to the formulation as above are coated with 2mg/tablet of a coating agent (this is a conventional coating agent suchas hydroxypropylmethylcellulose, macrogol or silicone resin) to obtaindesired coated tablets. (The same is applied to tablets mentionedbelow.) Desired tablets can be obtained by changing the amounts of thepresent compound and the additives appropriately.

[1833] 2) Capsule Formulation 1 in 150 mg Present compound  5 mg Lactose145 mg

[1834] Desired capsules can be obtained by changing the mixing ratio ofthe present compound to lactose appropriately.

[1835] 3) Eyedrops Formulation 1 in 10 ml Present compound  1 mgConcentrated glycerin 250 mg Polysorbate 80 200 mg Sodiumdihydrogenphosphate dihydrate  20 mg 1 N Sodium hydroxide q.s. 1 NHydrochloric acid q.s. Sterile purified water q.s.

[1836] Desired eyedrops can be obtained by changing the amounts of thepresent compound and the additives appropriately.

[1837] Pharmacological Test

[1838] 1) Chymase Inhibitory Effect

[1839] Chymase (enzyme) causes angiotensin I (substrate) to liberate adipeptide (His-Leu) by the enzyme reaction with the substrate. It wasreported that an enzymatic activity of chymase can be measured bymeasuring fluorescence intensity of the resulting peptide (Biochem.Biophys. Res. Com., 149 (3) 1186 (1987)). Since drugs having chymaseinhibitory activities suppress this liberation of the dipeptide, thechymase inhibitory activities of the drugs can be measured by measuringfluorescence intensity. In the present pharmacological test, chymaseinhibitory effects of the present compounds were studied by usingchymase extracted from a dog cardiac tissue (J. Biol. Chem., 265 (36),22348 (1990)).

[1840] Experimental Method

[1841] [1. Preparation of Chymase Enzyme Solution]

[1842] 1. A beagle is killed by drawing blood under Nembutal anesthesia,a heart is enucleated, and left ventricle is separated.

[1843] 2. This left ventricle is finely minced, and the tissue weight ismeasured.

[1844] 3. A 0.02 M Tris-HCl buffer (pH 7.4) is added to the tissue in anamount of 10 times by volume the tissue weight. The obtained mixture ishomogenized at 8,000 rpm for 20 seconds and then centrifuged at 4° C.and 21,000 rpm for 30 minutes, and the resulting supernatant isdiscarded.

[1845] 4. The same procedure as the above 3 is repeated twice for theresidue. Then, a 0.02 M Tris-HCl buffer (pH 7.4) containing 1% TritonX-100 and 0.01 M potassium chloride is added to the residue in an amountof 10 times by volume the amount of the residue. The obtained mixture ishomogenized at 8,000 rpm for 20 seconds, then incubated at 4° C. for onehour and centrifuged at 21,000 rpm for 30 minutes, and the supernatantis discarded.

[1846] 5. A 0.02 M Tris-HCl buffer (pH 7.4) containing 1% Triton X-100and 0.5 M potassium chloride is added to the residue in an amount of 10times by volume the amount of the residue. The obtained mixture ishomogenized at 8,000 rpm for 20 seconds, then incubated at 4° C. for onehour and centrifuged at 21,000 rpm for 30 minutes, and the supernatantis discarded.

[1847] 6. A 0.02 M Tris-HCl buffer (pH 7.4) containing 1% Triton X-100and 2.0 M potassium chloride is added to the residue in an amount of 10times the amount of the residue. The obtained mixture is homogenized at8,000 rpm for 20 seconds, then incubated at 4° C. for one hour andcentrifuged at 21,000 rpm for 30 minutes. The obtained supernatant isused as a chymase enzyme solution.

[1848] [2. Preparation of Reaction Buffer]

[1849] Tris-HCl and disodium ethylenediaminetetraacetate are dissolvedin water so that their concentrations are 92.3 mM and 12.0 mMrespectively to prepare a reaction buffer adjusted to pH 8.

[1850] [3. Preparation of Substrate Solution]

[1851] Angiotensin I is dissolved in water to prepare a 1.54 mMsubstrate solution.

[1852] [4. Preparation of Test Compound Solution]

[1853] A test compound is dissolved in dimethyl sulfoxide to prepare3.0×10⁻³M, 3.0×10⁻⁴ M, 3.0×10⁻⁵ M and 3.0×10⁻⁶ M test compoundsolutions.

[1854] [5. Measurement of Chymase Enzymatic Activity]

[1855] 1. The reaction buffer (32.5 μl), the substrate solution (75.0μl), the chymase enzyme solution (37.5 μl) and the test compoundsolution (5 μl) are mixed.

[1856] 2. The obtained mixture is incubated at 37° C. for one hour.

[1857] 3. To the mixture is added 15% trichloroacetic acid (225 μl), andthe whole is centrifuged at 4° C. and 14,000 rpm for five minutes.

[1858] 4. The supernatant is taken out. A 1%orthophthalaldehyde/methanol solution (165 μl) is added to 300 μl ofthis supernatant, and the whole is stirred and allowed to stand at roomtemperature for 10 minutes.

[1859] 5. 1.5 M Hydrochloric acid (300 μl) is added to the resultingmixture, and the whole is stirred and centrifuged at 4° C. and 14,000rpm for two minutes.

[1860] 6. The supernatant is taken out and irradiated with light havinga wavelength of 340 nm, and fluorescence intensity is measured at awavelength of 455 nm.

[1861] The blank of this test is defined as follows. The same proceduresas in the above 1 to 6 are repeated provided that a 20 m1M Tris-HClbuffer (pH 7.4, 37.5 μl) containing 1% Triton X-100 and 2.0 M potassiumchloride is used instead of the chymase enzyme solution (37.5 μl), anddimethyl sulfoxide (5 μl) is used instead of the test compound solution(5 μl) in the above 1. The obtained absorbance is the blank value. Thecontrol of this test is defined as follows. The same procedures as inthe above 1 to 6 are repeated provided that dimethyl sulfoxide (5 μl) isused instead of the test compound solution (5 μl) in the above 1. Theobtained absorbance is the control value.

[1862] [6. Calculation of Chymase Inhibition Rate]

[1863] Chymase inhibition rates of the test compounds are calculated bythe following equation from the measured fluorescence intensity.$\begin{matrix}{{{Chymase}\quad {inhibition}\quad {{rate}{\quad \quad}(\%)}} = \left\lbrack {1 - \left( {{Fluorescence}\quad {intersity}\quad {in}}\quad \right.} \right.} \\{{{using}\quad {test}\quad {compound}}\quad} \\{{{solution} - {{Blank}\quad {fluorescence}}}} \\{\left. {intensity} \right)/\left( {{Control}\quad {fluorescence}} \right.} \\{{{intensity} - {{Blank}\quad {fluorescence}}}} \\{\left. \left. {intersity} \right) \right\rbrack \times 100}\end{matrix}$

[1864] [7. Results]

[1865] Concentrations required to inhibit a chymase enzymatic activityby 50% were calculated from the obtained chymase inhibition rates of thetest compounds.

[1866] As examples of test results, Table 1 shows concentrations of thefollowing test compounds (Compound Nos. 2-22, 2-31, 2-32, 2-34, 2-46,2-47, 2-48, 2-63, 2-65, 4-1 and 10-7) required to inhibit the chymaseenzymatic activity by 50%, i.e., IC₅₀. TABLE 1 Test compound IC₅₀ (M)Compound No. 2-22 0.20 × 10⁻⁶ Compound No. 2-31 0.21 × 10⁻⁶ Compound No.2-32 0.36 × 10⁻⁶ Compound No. 2-34 0.25 × 10⁻⁶ Compound No. 2-46 3.80 ×10⁻⁶ Compound No. 2-47 0.50 × 10⁻⁶ Compound No. 2-48 1.20 × 10⁻⁶Compound No. 2-63 0.32 × 10⁻⁶ Compound No. 2-65 0.28 × 10⁻⁶ Compound No.4-1 1.50 × 10⁻⁶ Compound No. 10-7 0.37 × 10⁻⁶

[1867] Table 1 shows that the present compounds exhibited excellentchymase inhibition effects.

[1868] From the above-mentioned results, the present compounds areexpected to be useful as drugs, particularly to be effective in treatingvarious diseases originating from chymase such as cardiac infarction,heart failure, blood-vessel restenosis after PTCA, hypertension,diabetes complication, allergic diseases and asthma.

INDUSTRIAL APPLICABILITY

[1869] The present invention relates to novel3-oxo-3,4-dihydro-2H-1,4-thiazine derivatives or2-oxo-1,2,3,4-tetrahydropyrazine derivatives. These derivatives areexpected to be effective in treating various diseases caused by chymasesuch as cardiac infarction, heart failure, blood-vessel restenosis afterPTCA, hypertension, diabetes complication, allergic diseases and asthma.

1. A compound represented by the following formula [I]or a salt thereof,

wherein X is S. R¹ and R², being the same or different, are hydrogen, lower alkyl, cycloalkyl or aryl, R³ and R⁴, being the same or different, are hydrogen, lower alkyl, cycloalkyl, aryl or an aromatic heterocycle, R⁵ is hydrogen, lower alkyl, cycloalkyl, aryl or -A₃-A₄-R⁷, R⁶ is hydrogen, lower alkyl, cycloalkyl, hydroxy, lower alkoxy, aryl, aryloxy or an aromatic heterocycle, R⁷ is hydrogen, lower alkyl, hydroxy, lower alkoxy, aryl, aryloxy, amino, lower alkylamino, arylamino, an aromatic heterocycle or a nonaromatic heterocycle, n is 0 or 1, A₁ is lower alkylene, A₂ is carbonyl or sulfonyl, A₃ is lower alkylene, A₄ is carbonyl or oxalyl, each lower alkyl defined above is unsubstituted or substituted by halogen, hydroxy, lower alkoxy, aryl or aryloxy. each lower alkoxy defined above is unsubstituted or substituted by aryl, and each lower alkylene defined above is unsubstituted or substituted by aryl.
 2. The compound or a salt thereof as claimed in claim 1, wherein R⁷ is a nonaromatic heterocycle selected from the group consisting of pyrrolidine, pyrroline, tetrahydrofuran, dihydrofuran, tetrahydrothiophene, dihydrothiophene, imidazolidine, imidazoline, oxazolidine, oxazoline, 4,4-dimethlyloxazoline, thiazolidine, thiazoline, 5,5-dimethylthiazoline, pyrazolidine, pyrazoline, piperidine, tetrahydropiperidine, dihydropiperidine, tetrahydropyran, dihydropyran, pyran, piperazine, morpholine, thiomorpholine, homopiperidine, homopiperazine and homomorpholine; or R⁷ is an aromatic heterocycle selected from the group consisting of pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, isoxazole, isothiazole, pyridine, pyrazine, pyrimidine, indole, isoindole, benzimidazole, benzoxazole, benzothiazole and quinoline.
 3. The compound or a salt thereof as claimed in claim 1, wherein n is 1 in the formula [I].
 4. The compound or a salt thereof as claimed in claim 3 wherein R⁶ is lower alkyl, aryl or an aromatic heterocycle in the formula [I].
 5. The compound or a salt thereof as claimed in claim 4, wherein R³, R⁴. R⁶ or R⁷ is an aromatic heterocycle selected from the group consisting of pyridine and thiophene.
 6. The compound or a salt thereof as claimed in claim 1, wherein R⁵ is -A₃-A₄-R⁷, and A₃ is lower alkylene which is unsubstituted or substituted by phenyl in the formula [I].
 7. The compound or a salt thereof as claimed in claim 6, wherein R⁷ is lower alkyl, lower alkoxy, an aromatic heterocycle or a nonaromatic heterocycle in the formula [I].
 8. The compound or a salt thereof as claimed in claim 7, wherein R⁷ is a nonaromatic heterocycle selected from the group consisting of pyrrolidine, dihydrofuran, oxazolidine, 4,4-dimethyloxazoline, thiazoline, 5,5-dimethylthiazoline, piperidine, piperazine and morpholine; or R⁷ is an aromatic heterocycle selected from the group consisting of oxazole, thiazole and benzothiazole.
 9. A pharmaceutical composition comprising a pharmaceutically effective amount of the compound or a salt thereof as claimed in claim 1 as an active ingredient in combination with a pharmaceutically acceptable carrier.
 10. A compound represented by the following formula [II] or a salt thereof,

wherein X is S, R¹ and R², being the same or different, are hydrogen, lower alkyl, cycloalkyl or aryl, R³ and R⁴, being the same or different, are hydrogen, lower alkyl, cycloalkyl, aryl or an aromatic heterocycle, R⁶ is hydrogen, lower alkyl, cycloalkyl, hydroxy, lower alkoxy, aryl, aryloxy or an aromatic heterocycle, R⁷ is hydrogen, lower alkyl, hydroxy, lower alkoxy, aryl, aryloxy, amino, lower alkylamino, arylamino, an aromatic heterocycle or a nonaromatic heterocycle, n is 0 or 1, A₁ is lower alkylene, A₂ is carbonyl or sulfonyl, A₃ is lower alkylene, Q is —CH(OH)CO— or —CH(OH)—, each lower alkyl defined above is unsubstituted or substituted by halogen, hydroxy, lower alkoxy, aryl or aryloxy, each lower alkoxy defined above is unsubstituted or substituted by aryl, and each lower alkylene defined above is unsubstituted or substituted by aryl.
 11. A method of inhibiting chymase in a patient comprising administering to a patient in need thereof a pharmaceutically effective amount of the compound or a salt thereof according to claim 1, alone or in combination with a pharmaceutically acceptable carrier.
 12. The method as claimed in claim 11, wherein the administering to a patient is carried out orally.
 13. The method as claimed in claim 11, wherein the administering to a patient is carried out parenterally.
 14. The method as claimed in claim 11, wherein the administering to a patient is carried out by applying eyedrops. 